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Opportunities and Challenges in Developing Stearoyl-Coenzyme A Desaturase‑1 Inhibitors as Novel Therapeutics for Human Disease Miniperspective Zaihui Zhang,† Natalie A. Dales,‡ and Michael D. Winther*,§ †

Signalchem Lifesciences Corp., 550-5600 Parkwood Way, Richmond, British Columbia, V6V 2M2, Canada Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States § Xenon Pharmaceuticals Inc, 3650 Gilmore Way, Burnaby, British Columbia, V5G 4W8, Canada ‡

ABSTRACT: This review provides an overview of stearoylcoenzyme A desaturase-1 (SCD1) as a novel therapeutic target for metabolic disorders and other indications. Target validation is reviewed, and limitations due to incomplete knowledge of the relevant biological systems are described. Assay development, particularly for high throughput screening, and characterization of SCD1 inhibition are summarized. The progress and evolution in medicinal chemistry are discussed, specifically focusing on key attributes of the most advanced SCD1 inhibitors described in the primary literature and in patent applications. This work culminated in numerous companies identifying potent selective inhibitors, some of which progressed to early clinical development. The status of current SCD1 drug discovery programs is reviewed. Challenges are discussed, and potential new directions are indicated.

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INTRODUCTION

BIOLOGY Identifying New Targets for Drug Development. Medicinal chemists are adept at discovering small molecule modulators that selectively and potently interact with diverse targets of interest. The key is identifying suitable biological targets for the application of these elegant medicinal chemistry methods. With over 20 000 protein-coding genes to choose from, a number of approaches have been utilized to determine which biological processes are most suitable for pharmacological intervention. These approaches include metabolomics, proteomics, genetic studies in model organisms (Caenorhabditis elegans, Drosophila melanogaster, Mus musculus), and human genetic studies. Over the past decade, drug development efforts have been increasingly based on this paradigm.1 Unfortunately, for each success, there are numerous failures. Molecules and targets have failed to live up to their promise because of the inherent complexity of biological systems and pathways, the lack of translatability of genetic studies in laboratory species, as well as difficulty translating in vitro systems to animal models and human disease settings.2 In an effort to de-risk the drug discovery process, many researchers have focused efforts on using human genetic investigations to discover and validate new drug targets. This approach has been effective in advancing promising new therapies in LDL lowering.3 In the case of SCD1, the human data obtained for target validation are primarily based on biochemical studies that

Over the past decade publications from over a dozen academic and industrial research groups have described the identification and attributes of small molecule inhibitors of stearoyl-coenzyme A desaturase-1 (SCD1). This extensive chemistry effort was triggered by pioneering studies that identified SCD1 as a potential target for the development of novel therapies for metabolic diseases. Despite the discovery of many potent, selective inhibitors with good pharmacokinetic properties from multiple scaffolds, successful clinical development has been elusive. This challenge is in part due to mechanism-based side effects that limit therapeutic utility and to incomplete understanding of the SCD1 target biology. Recent approaches toward tissue-selective SCD1 inhibitors, specifically livertargeted inhibitors, provide compounds with improved safety margins with respect to mechanism-based adverse effects in animal models; however, these molecules do not appear to have solved the fundamental challenges posed by SCD1 biology. In view of these limitations in developing oral therapies for metabolic disease, emphasis has been placed on assessing SCD1 inhibitors in other indications and/or exploring local administration. In this review, we highlight the structural diversity and evolution of small molecule SCD1 inhibitors since 2005, when the first druglike SCD1 inhibitors were reported. We also describe the potential application of SCD1 inhibitors beyond metabolic diseases, where perhaps clinical utility can be demonstrated more readily. © 2013 American Chemical Society

Received: September 30, 2013 Published: December 2, 2013 5039

dx.doi.org/10.1021/jm401516c | J. Med. Chem. 2014, 57, 5039−5056

Journal of Medicinal Chemistry

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balance of saturated and unsaturated lipids, it has a profound effect on membrane fluidity and thus influences many membrane-bound biological processes and systems.5 SCD1 is also critically important in energy balance. Saturated fatty acids are utilized, or oxidized, preferentially over unsaturated fatty acids, which tend to be predominantly stored as fat in tissues (Figure 2). There are two other important fatty acid desaturases that are involved in related lipid pathways. The enzymes Δ6 desaturase (D6D) and Δ5 desaturase (D5D) catalyze the desaturation of monounsaturated fatty acids to produce polyunsaturated fatty acids (PUFA). These two enzymes utilize the same protein accessories used by SCD1: NADH-cytochrome b5 reductase and cytochrome b5. As it may not be desirable to inhibit D6D and D5D, these enzymes are important early counterscreens in any drug discovery program. Rodent Genetic Studies of SCD1. While the biochemical role of SCD1 as the rate-limiting step of monounsaturated fatty acid (MUFA) biosynthesis from saturated fatty acid (SFA) substrates was well-known since the 1970s,6 it was not until the late 1990s, when rodent genetic studies were undertaken, that the potential role of SCD1 in metabolic regulation was revealed. In the 1960s, a strain of mouse was identified that had a profound deficiency in sebaceous glands.7 Initially the interest in this target related to dermatological conditions, based on the observation that a strain referred to as the Ascebia mouse had reduced skin oil production, poor coat condition, and hair loss. Genetic studies later revealed that this phenotype was caused by a spontaneous deletion of the gene coding for SCD1.8 An unexpected and novel finding was that elimination of SCD1 activity had a profound effect on metabolic diseases. This became evident through the pioneering studies of James Ntambi and colleagues who showed that the SCD1-deficient mouse had greatly reduced levels of hepatic triglycerides and cholesterol esters.9 Subsequent studies provided evidence for additional metabolic benefits, including reduced weight gain on high fat diet.10 In collaboration with Jeffrey Friedman, Ntambi demonstrated a dramatic effect in normalizing the metabolism of leptin-deficient animals.11 In the leptin-deficient model for obesity, mice with an inactive SCD1 gene were significantly less obese than the control (ob/ob) mice and had a greater total and resting oxygen consumption.12 The SCD1 knockout mice had reduced triglyceride storage and VLDL production, and histologically normal livers, in stark contrast to the marked steatosis of the control (ob/ob) animals. Furthermore, improved insulin responsiveness has been shown in several animal models.13 Because of important differences in lipid metabolism between rodents and humans, gathering supporting human data corroborating SCD1 as a target for metabolic diseases was critical in justifying efforts to develop inhibitors for this enzyme. By use of surrogates of SCD1 activity, specifically desaturation indices, Ntambi and colleagues correlated enzyme activity with disease settings.14 These studies quickly attracted the interest of the pharmaceutical industry, and a number of projects targeting SCD1 were initiated, as evidenced by subsequent patent filings and publications on small molecule drug discovery from 2005 to 2013. Genetic Architecture of SCD Genes. The SCD1 gene family was first characterized in rodents, revealing four SCD genes in a single cluster on chromosome 19. However, in humans and other primates there are two SCD genes, SCD1 (on the long arm of chromosome 10), which is co-orthologous

provide correlative data to support the hypothesis that SCD1 up-regulation, leading to high levels of SCD protein, is associated with metabolic diseases (obesity, diabetes, fatty liver). However, the scarcity of known SCD1 gene mutations limits the impact of human genetics in identifying key drugtarget mechanisms and potential liabilities in humans. Role of SCD1 in Lipid Metabolism. SCD1 is an ironcontaining fatty acid desaturase that catalyzes the introduction of a double bond between carbons 9 and 10 of the stearic acid chain of stearoyl-CoA to form oleoyl-CoA. The enzymatic reaction is illustrated as follows: stearoyl‐CoA + 2 ferrocytochrome b5 + O2 + 2H+ = oleoyl‐CoA + 2 ferricytochrome b5 + 2H 2O

This enzyme is also referred to as a Δ9 desaturase (D9D), based on the exquisite selectivity of the location of the desaturation reaction at the ninth position on the acyl chain of the fatty acid of the substrate stearic acid (C18:0) to produce oleic acid (C18:1n9). SCD1 can also catalyze this same reaction with structurally related saturated fatty acid (SFA) substrateCoAs. For example, palmitate (C16:0) is converted to palmitoleate (C16:1n7), again as a CoA conjugate, by SCD1. This enzymatic oxidation occurs at the inner face of the endoplasmic reticulum in association with NADH-cytochrome b5 reductase, utilizing coupled electron transfers through cytochrome b5, FADH2, and NADH.4 The monounsaturated fatty acid (MUFA) products of SCD1 desaturation may be further elongated and/or desaturated within the cell and/or incorporated into a variety of complex lipids including triglycerides, phospholipids, wax esters, and other lipid species (Figure 1). As saturated fatty acid substrates are generally well

Figure 1. SCD1 enzyme complex introduces a single double bond at the 9 and 10 positions of long-chain acyl-CoAs for subsequent incorporation into complex lipids.

supplied by the diet and endogenous synthesis, the desaturation reaction catalyzed by SCD1 is the rate-limiting step in the production, and subsequent metabolism, of monounsaturated fatty acids in the body. There are multiple mechanisms whereby altering the lipid composition and SFA/MUFA ratio affects cellular functioning. Since SCD1 is an important enzyme in determining the cellular 5040



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Figure 2. SCD1 is believed to have a central role in directing the flow of lipid substrates between storage and utilization in energy metabolism. The objective in inhibiting SCD1 is to shift the flow of carbons from storage into oxidation pathways.

Biomarkers for SCD1 Activity. When the lipid composition of tissues is analyzed, it is common to express the data for each fatty acid as a percentage of the total fatty acids measured rather than as mg/g tissue. The desaturation index (DI) is the ratio of the MUFA product divided by the SFA substrate of the SCD1 enzymatic reaction. The DI has been shown in animal studies to correlate with SCD1 enzymatic activity.14 Desaturation indices can be measured from a variety of tissues and peripherally in plasma. This readout provides a convenient surrogate to evaluate SCD1 activity. Although dietary and other factors can influence the plasma lipid composition (and hence DI), there remains value in this readily measured biomarker, especially where other variables can be held constant. Pharmacological Target Validation. At the time the genetic studies revealed the role of SCD1 in metabolic disease no suitable small molecule tools targeting SCD1 were available to replicate the genetic findings. Substrate analogues that could block SCD1 catalytic activity, such as conjugated linoleic acid (CLA), thia-fatty acids (9-thiastearic acid) and cyclopropenoid fatty acids (sterculic acid), had been described, but these analogues either were not selective for SCD1 or had to be converted to CoA conjugates using intracellular machinery to be biologically active.20,21 These limitations precluded target validation using these tool molecules. Target validation with a pharmacological agent was accomplished using antisense oligonucleotides (ASO), which decreased SCD1 protein levels in the liver, reduced dietinduced obesity and steatosis, and improved insulin sensitivity, without eye or skin abnormalities.22 Gutierrez-Juarez et al.23 and Brown et al.24 extended these initial observations to show that treatment of rats with SCD1 ASO reversed the severe insulin resistance and hepatic steatosis that occur on a high-fat diet. The target discovery and validation studies described in the literature attracted investigators in industry and academia to invest in the discovery of small molecule SCD1 inhibitors. At the time SCD1 first emerged as a potential drug target no selective SCD1 inhibitors were available to serve as starting points for a medicinal chemistry programs. Therefore, attention turned toward high throughput screening (HTS) to identify early leads from large chemical libraries that could be developed into potent and selective SCD1 inhibitors.

to the four mice genes, and SCD5 which is located on chromosome 4, which does not have a rodent orthologue. By assessment of the SCD gene structure in multiple species, the appearance of the two SCD genes, SCD1 and SCD5, is thought to have occurred early in vertebrate evolution.15 Rodents show an expansion of the SCD1 family and loss of a functional SCD5 orthologue. Rodent SCD1 and human SCD1 are the dominant forms found in the liver and perform similar functions. SCD1 is the primary enzyme responsible for synthesis of MUFAs in each species and has been the principal isoform considered in drug discovery programs. The confirmation of the catalytic activity and biological role of SCD5 has been problematic, with no published reports for in vitro assays. The most direct indication that SCD5 may have Δ9 desaturase catalytic activity comes from the work of Sinner.16 The investigators overexpressed SCD5 in mouse Neuro2 cells and found an increase in 16:1n7, indicating an increase in Δ9 desaturation. They further observed that SCD5 expression stimulated neural cell growth and was involved in the regulation of neuronal cell growth and differentiation. Human Genetics. The genetic investigation of SCD1 in humans has involved examining correlations of genetic variation in the SCD1 gene with the occurrence of the metabolic syndrome. In this study, the authors identified a SNP that was significantly associated with an increased prevalence for metabolic syndrome;17 however, this result was not replicated in one European cohort.18 One important limitation of these studies is that the polymorphisms tested do not have a significant impact on SCD1 expression or activity; therefore, an impact on metabolic disease or other health outcomes might not be expected. More extensive genetic screening would be needed to identify mutations with a more profound effect on SCD activity to asses function in such studies. As noted earlier, the low frequency of mutations in the SCD1 gene that significantly reduces or eliminates SCD1 activity has hindered the utilization of human genetic studies to directly access impact of reducing SCD1 (or SCD5) in humans. Although there is one report in which a chromosomal pericentric inversion that disrupts the SCD5 gene was associated with a familial case of cleft lip, the direct implication of SCD5 in this condition has not been confirmed.19 A more complete understanding of the enzymatic activity and biological functions of SCD5 remains an outstanding issue in the field. 5041



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Figure 3. Summary of the number of publications including patent applications, scientific papers, and conference presentations on small molecule SCD1 inhibitors from 2005 to April 2013.

Figure 4. Evolution of potent, selective pyridazinylpiperazine based SCD1 inhibitors from a pyridine-2-ylpiperazine scaffold (Xenon).

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SCD1 INHIBITORS Screening. As mentioned above, no small molecule inhibitors or starting points for medicinal chemistry existed in 2000. Furthermore, difficulties crystallizing the membranebound form of SCD1 meant that crystal structures could not readily be generated to guide the search for small molecule inhibitors. Thus, HTS was the most viable approach to identify suitable scaffolds for a medicinal chemistry program. At that time, the standard assays in use to detect SCD1 activity required radiolabeled fatty acids, which then had to be separated by chromatography to resolve substrates and products of desaturation reactions.25 A greatly improved assay was developed using a specialized radiolabeled substrate containing tritium atoms on the C9 and C10 carbons of stearic acid. Use of this labeled substrate in the enzymatic reaction results in the production of a molecule of labeled water. A simple separation of the fatty acid substrate from the labeled H2O product enables the rapid measurement of enzyme acrtivity.26 Although this assay is effective in an HTS format, caution is required in conducting detailed biochemical studies using this substrate because of kinetic isotope effects.4 Other assay formats described include methods based on mass spectrometry with a deuterium-labeled substrate27 and a scintillation proximity assay using a tritium-labeled SCD1 inhibitor.28 The first selective, druglike small molecule SCD1 inhibitors were disclosed in a series of patent applications by Xenon Pharmaceuticals Inc. in 2005.29−34 Since that time, many other small molecule SCD1 inhibitors have been reported in patent applications, scientific papers, and conference presentations. Figure 3 illustrates the publication trend from 2005 to April

2013. Not surprisingly, the initial phase of disclosed SCD1 inhibitors appeared in patent applications, which peaked in 2008. This peak was then followed by a rise in papers and presentations starting in 2009. Recently, Liu published review articles on SCD1 inhibitors for dyslipidemia and obesity.35,36 Xenon and Novartis. Xenon started its discovery of small molecule SCD1 inhibitors for the treatment of obesity and metabolic syndrome with a high throughput screening campaign that identified a number of pyridin-2-ylpiperazine compounds with micromolar activity against mouse SCD1. Compound 1 (Figure 4) was the most potent inhibitor identified with mSCD IC50 of 5.1 μM. A focused compound library of ∼600 compounds (21 amines and 28 carboxylic acids) was synthesized to develop basic SAR trends.29,37 Several preferred amines and carboxylic acids were identified, and many potent SCD1 inhibitors were discovered from this library. Compound 2 (Figure 4) was the most potent with an IC50 of 78 nM against mSCD1 and 100 nM in a HepG2 cell-based assay. Lead optimization efforts around this pyridin-2ylpiperazine scaffold started with the replacement of the pyridin-2-yl moiety. A series of analogues were prepared and tested, and the best results were obtained with pyridazine replacement (compound 3, Figure 4) which improved the potency by about 3-fold with an IC50 of 26 nM against mSCD1 and 37 nM in the HepG2 assay. This compound possessed druglike properties and demonstrated a robust in vivo pharmacodynamic response inhibiting rat liver SCD1 activity by about 40% at 4 h after final dose after 2 days of once daily dosing intraperitoneally (ip) at 15 mg/kg. Further optimization effort led to the discovery of a novel, potent, selective, and orally bioavailable piperazinylpyridazine inhibitor 4 (XEN103). 38 Compound 4 was highly active in vitro 5042



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Figure 5. Other pyridazine-based SCD1 inhibitors disclosed by Xenon.

Figure 6. Thiazole-based SCD1 inhibitors discovered by Xenon.

Figure 7. Pyridine- and pyrazole-based SCD1 inhibitors disclosed by Xenon.

therapeutic applications in diabetes and metabolic diseases. In search of structurally distinct SCD1 inhibitors from the pyridazine-based SCD1 inhibitors, another HTS was conducted and a structurally distinct scaffold, 2-aminothiazoles exemplified by compound 13 (Figure 6), was identified.47 Optimization of this scaffold led to the discovery of thiazole-based SCD1 inhibitors published in several patent applications between 2008 and 2009: thiazolylimidazolidinones,48,49 thiazolyltriazonones,48,49 thiazolylpyridinones,50 thiazolylpyrrolidinones and thiazolylpiperidinones, 50 and thiazoleheteroaryl compounds.51,52 These new scaffolds provided structural diversity in the developing SCD1 inhibitor field. Other scaffolds discovered via scaffold morphing by Xenon/ Novartis include the pyridineimidazolidinones,53 pyridinetriazolones,53 pyridine-based spiro compounds,54 and pyrazole-

(mSCD1 IC50 = 14 nM and HepG2 IC50 = 12 nM) and showed a good pharmacodynamics effect in vivo (ED50 = 0.8 mg/kg). Compound 4 also demonstrated striking reduction of body weight gain in a rodent model.38 In a separate mouse model, compound 4 induced pronounced sebaceous gland atrophy after topical application in a dose- and time-dependent manner in mouse skin.39 Further exploration of pyridazine-based SCD1 inhibitors revealed that the amide, pyridazine, and piperazine moieties could be replaced with certain heteroaryl or heterocyclyl groups without dramatic impact on the potency against SCD1. These findings were disclosed by Xenon in a number of patent applications in 2006.40−46 A small set of examples is illustrated in Figure 5. In 2004, Xenon and Novartis formed a collaboration working together toward the development of SCD1 inhibitors for 5043



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based compounds.55 These compounds are also potent and selective SCD1 inhibitors (Figure 7). Merck Frosst. Merck Frosst disclosed a series of thiadiazole- and thiazole-based SCD1 inhibitors in a patent application in 2006,56 and the pharmacological evaluations of these compounds were later reported.57,58 Representative structures are illustrated in Figure 8. Compound 33 was

were found to be systemically distributed and mechanism-based skin and eye adverse effects manifested in chronic studies.59−63 Abbott. On the basis of the piperazinylpyridazine and piperazinylpyridine scaffolds reported by Xenon Pharmaceuticals, Abbott scientists applied scaffold design strategies and developed a series of 1-(4-phenoxypiperidin-1-yl)-2-arylaminoethanones,64 pyridazine heteroaryl-based65 and piperidine arylurea-based SCD1 inhibitors.66,67 Both compounds 41 and 42 (Figure 10) were potent inhibitors of human SCD1 activity

Figure 8. Thiadiazole- and thiazole-based SCD1 inhibitors disclosed by Merck Frosst.

Figure 10. SCD1 inhibitors reported by Abbott.

identified as a tool compound to investigate SCD1 biology in animals. Compound 33 was obtained by replacing the sixmembered pyridazine ring with a five-membered thiazole ring of the piperazinylpyridazine analogues reported earlier (see Figure 4, Xenon). This compound demonstrated in vitro potency against SCD1 with IC50 values of 0.1 μM against rSCD and 0.3 μM against hSCD1 and no Δ5 and Δ6 desaturase activity. After oral administration, compound 33 decreased the mouse liver SCD activity index in a dose-dependent manner with ED50 of 3 mg/kg in an acute study. Also, in a 7-week chronic mouse study, compound 33 reduced body weight gain by 73%; however, partial eye closure and progressive alopecia appeared after 14 days of treatment.57 These findings were similar to the phenotype observed in the SCD1-deficient mouse and may indicate a mechanism-based toxicity. Compound 34, a highly potent SCD inhibitor (HepG2 IC50 = 1 nM), was identified from the optimization efforts. Compound 34 demonstrated a dose dependent reduction of liver SCD activity index in mice with an ED50 of 0.3 mg/kg. In a 4-week chronic study with oral dosing at 0.2 mg/kg, compound 34 demonstrated a robust 24% reduction of body weight gain in mice fed a high fat diet. This result was accompanied by an improved metabolic profile as shown by changes in insulin and glucose levels, but the mechanism-based eye and skin adverse effects were also observed.58 During their optimization process of the thiazole lead, several other scaffolds were also investigated and are summarized in Figure 9. These compounds were potent SCD1 inhibitors with IC50 against rSCD1 in the range of 2−80 nM. All compounds

with IC50 values of 90 and 93 nM, respectively, in a biochemical assay. SAR investigation indicated that only small substituents such as methyl and ethyl were tolerated on the primary amide.64 Compound 43 (Figure 10) was shown to be selective for SCD1 and to possess a good PK profile. Compound 43 also demonstrated robust cellular activity by inhibiting the conversion of saturated LCFA-CoA to monounsaturated LCFA-CoA in HepG2 cells.65 The urea analogue, compound 44 (A-939572, Figure 10), was also a potent and selective SCD1 inhibitor with an IC50 of 90% inhibition of human SCD1 activity in a microsomal assay at 10 μM. No IC50 values were disclosed. Interestingly, compound 56 was reported to be selective for liver over skin in terms of compound exposure.79

plasma triglycerides in Zucker fatty rats after a 7-day oral administration.68 Further elaboration of this structure by the cyclization of the benzoylpiperidine to form a spirocyclic system, such as compounds 46 and 47 (Figure 11), afforded a series of highly potent spiropiperidine-based SCD1 inhibitors with subnanomolar IC50 values. Compounds 46 and 47 were 0.01 and 0.06 nM in mouse liver microsomes and 0.01 and 0.03 nM in human microsomes, respectively.69−71 Compound 47 was also highly potent in a cell-based assay with an IC50 value of 0.6 nM. Furthermore, compound 47 demonstrated a reduction of plasma desaturation index in C57BL/6J mice on a nonfat diet after a 7-day oral administration, without causing notable abnormalities in the eyes or skin up to the highest dose of 3 mg/kg.69 Daiichi Sankyo also developed a series of 2aminothiazole-based SCD1 inhibitors such as compounds 49 and 50 (Figure 11) from the hit compound 48.72,73 Compound 5045



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Figure 14. Piperazine-based SCD1 inhibitors reported by Forest Laboratories.

Sanofi-Aventis. On the basis of the structures of the SCD1 inhibitors published by Xenon Pharmaceuticals and Merck Frosst, Sanofi-Aventis applied rescaffolding strategies to modify the piperidine moiety, leading to the discovery of hexahydropyrrolopyrrole based SCD1 inhibitors.80,81 Another scaffold, benzimidazolecarboxamide, was also disclosed by SanofiAventis.82 Examples of the Sanofi-Aventis scaffolds are shown in Figure 13. Some of the compounds, such as compounds 60 and 61, exhibited 100% inhibition of SCD1 activity at 10 μM in a biochemical assay. Compound 62 was the optimized representative example with desirable in vitro potency (enzymatic IC50 of 8.5 nM with rat liver microsomes and cellular IC50 of 39 nM in HepG2 cells), selectivity, and favorable overall properties. The pharmacological properties of compound 62 were also described.83 In vivo, compound 62 reduced serum desaturation index, decreased body weight gain, and improved lipid parameters and blood glucose levels of obese Zucker diabetic fatty rats treated orally at 20 mg/kg for 4 weeks. However, target-related adverse effects, such as fissures of the eyelid, alopecia, and inflammation of the skin were observed from day 11 to the end of study.83 Another series of Sanofi-Aventis compounds, exemplified by compound 63, was discovered using ligand-based virtual screening, followed by optimization of the benzimidazolecarboxamide scaffold.84 Compound 63 inhibited SCD1 activity with an IC50 of 0.136 μM in an enzymatic assay and 0.157 μM in a HepG2 cell-based assay. In vivo studies indicated that this compound significantly decreased the serum fatty acid desaturation index compared to vehicle in obese animals 6 h after oral dosing at 30 mg/kg.84 Forest Laboratories. Forest Laboratories reported the discovery of a series of piperazine-based SCD1 inhibitors in a number of patent applications from 2008 to 2010.85−88 Some examples of these piperazine-based SCD1 inhibitors are illustrated Figure 14. No biological data were reported in these published applications. Smithkline Beecham/GlaxoSmithKline. A series of tetrahydroisoquinolinecarboxamides, triazole derivatives, and tetrahydronaphthyridine derivatives stearoyl-CoA desaturase inhibitors were disclosed by Smithkline Beecham in a number of patent applications from 2008 to 2009, and the representative structures are illustrated in Figure 15.89−96 Most of the compounds were reported to have pIC50 of greater than 5.5 in the 3H2O release biochemical assay using rat liver

Figure 15. Tetrahydroisoquinolinecarboxamide SCD inhibitors reported by Smithkline Beecham.

microsomes. Compound 70 was the only compound disclosed in one of the patent applications, and its pIC50 was reported to be >5.5 in a biochemical assay and between 7.00 and 7.25 in a HepG2 cell-based assay. 91 Another compound 75 was evaluated in great detail in in vitro assays and in vivo models.97 This compound inhibited SCD1 activity with an IC50 of 0.18 μM in a biochemical assay and was reported to inhibit SCD1 activity in human hepatocytes, human adipocytes, and human skeletal muscles. In Zuckerfa/fa rats, a marked reduction in hepatic lipids and a significant improvement of glucose tolerance were observed with compound 75 treatment at 50 mg/kg q.d. by oral administration for 11 days. In a diet-induced insulin resistant rat model, a very strong reduction in Tritoninduced hepatic VLDL-triglyceride production was induced by compound 75 after 2-week oral treatment at 50 mg/kg q.d. An improvement in whole body insulin sensitivity, as reflected by an increase in the glucose infusion rate, was also observed following a hyperinsulinemic−euglycemic clamp in animals treated with compound 75. It is worth noting that no targetrelated adverse effects, such as dry skin and dry eyelids, were observed after 4 weeks of treatment with compound 75 in this study.97 CV Therapeutics/Gilead. CV Therapeutics conducted a screen of about 5.2 million compounds and identified moderately active SCD inhibitors such as pteridinone 5046



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Figure 16. SCD1 inhibitors discovered by CV Therapeutics from pteridinone and aniline HTS hits.

Figure 17. SCD1 inhibitors reported by Japan Tobacco Company.

Figure 18. SCD1 inhibitors reported by Pierre Fabre Medicament.

compounds98,99 (compound 76, Figure 16) and aniline compounds100−102 (compound 77, Figure 16). On the basis of compound 76, modification of the central bicyclic core led to the discovery of several bicyclic scaffolds the most potent of which, compound 78 (Figure 16), had an IC50 of 50 pM in a HepG2 SCD assay.98 Compound 78 was shown to be metabolically stable and selective against Δ5 and Δ6 desaturases. Compound 79 (Figure 16) was obtained from the optimization effort of the aniline hit compound 77 by

replacing the benzene ring core with a quinazolin-4-one core. Compound 79 had an IC50 of 119 nM in a cell-based HepG2 SCD assay and had 90% oral bioavailability in rat with excellent plasma exposure. Additionally, compound 79 demonstrated moderately selective liver distribution and significantly reduced SCD activity in plasma and liver in a 5-day study in rats on a high sucrose diet.100 By merging of the structural features of the two CV Therapeutics series described above, the highly potent hybrid compound 80 (Figure 16) emerged with an IC50 value 5047



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effects, Pfizer scientists identified an acylguanidine HTS hit compound 107 from a RapidFire high-throughput mass spectrometry (RF-MS) assay.112 The original hit compound 107 demonstrated reasonable potency on SCD1 with an IC50 value of 94 nM in a rSCD1 assay and 217 nM in a hSCD1 assay. After a series of optimization efforts, the Nbenzylimidazolecarboximde compound 108 was discovered as a potent inhibitor of SCD1 (rSCD1 IC50 = 11.7 nM) with a favorable pharmacokinetic profile (52% oral bioavailability and t1/2 of 2.3 h after oral dosing in rat). Compound 108 demonstrated a dose-dependent plasma DI reduction in rats. However, mild to moderate effects on ocular tissue were also observed in the study, indicating manifested mechanism-based side effects.112 Pfizer also disclosed a single SCD inhibitor (compound 109, Figure 20) in a patent application in 2009 and claimed it for dermatological conditions.113 Compound 109 was highly potent with an IC50 value of 5.8 nM in microsomal assay and 6.8 nM in human adipocyte assay. In a hamster ear model, compound 109 demonstrated a dose-related change in sebaceous gland size and number, and the EC50 was determined to be 0.3% (0.025 mg/cm3) based on reduction of wax ester production after 2-week topical b.i.d. applications.113 Others. Hoffmann-La Roche reported a series of benzylpiperizinylpyrimidinones as SCD1 inhibitors (compounds 110, 111, and 112; Figure 21)114 with IC50 values ranging from submicromolar to nanomolar. Also, a series of pyrazolopyrimidine analogues (compounds 113, 114, and 115; Figure 21) were described in patent applications by Biovitrium.115 These compounds demonstrated submicromolar activity against SCD1. No other pharmacological data were reported for these compounds. Fajas et al. disclosed a series of arylsulfonylpiperazine compounds (compounds 116 and 117, Figure 21), and they were reported to be used for anticancer therapy, specifically for prostate cancer therapy.116 SAR Characteristics of Systemic Inhibitors. A large number of potent, selective SCD1 inhibitors have been reported over the past 8 years from a number of research groups. Most of the potent SCD1 inhibitors reported to date share several structural features. These inhibitors tend to be small (MW < 500), linear, lipophilic, and somewhat rigid and share a general pharmacophore. Presumably, these inhibitors mimic the shape of the lipid the SCD1 enzyme handles. There is also a prevalence of a privileged fragment as shown in the following where the preferred R group is an electronwithdrawing group, such as F or CF3:

of 6 nM in a cell-based HepG2 SCD assay. Compound 80 was preferentially distributed into liver (liver/plasma ratio of 76 at 2 h after oral dosing of 5 mg/kg) and significantly reduced SCD activity in a dose-dependent manner in plasma and liver in a 5day study in rats on a high sucrose diet.103 Japan Tobacco Company. Japan Tobacco Company disclosed a series of five-membered heteroaryl, amidecontaining compounds (81 and 82 in Figure 17),104 heteroaryl, urea-containing compounds (83−86 in Figure 17),105 and aryl, amide-containing compounds (87 and 88 in Figure 17)106 in three patent applications published in 2008. All compounds listed in Figure 17 were reported to have SCD1 inhibitory effects with IC 50 < 0.1 μM. No further results or pharmacological investigations were reported. Pierre Fabre. More recently, Pierre Fabre Medicament reported several SCD1 inhibitors as illustrated in Figure 18.107−109 These SCD1 inhibitors retained a key structural feature of earlier reported potent and selective SCD1 inhibitors, the substituted phenoxypiperidine moiety. The compounds depicted below were reported to have greater than 95% inhibition of SCD1 activity at 10 μM; however, no pharmacological data were reported. Takeda. Takeda reported a number of different scaffolds with SCD1 inhibitory activity (Figure 19), including, arylamides

Figure 19. SCD1 inhibitors discovered by Takeda.

(compounds 98−101),110 spiropiperidine pyridazines (102 and 103), and spiropyrrolidinepyridazine compounds (104 and 105).111 The reported inhibitory activity of these compounds against SCD1 in a rat liver microsomal assay was in the range of 90−100% inhibition at 10 μM. No other data or pharmacological results were reported for these compounds. Pfizer. To seek a potent tool compound from a chemical class distinct from the pyridazine-based SCD1 inhibitor (compound 106, Figure 20) to discern mechanism-based side

Liver-Targeting SCD1 Inhibitors. It is evident that potent, systemically distributed SCD1 inhibitors result in mechanismbased adverse effects such as dry skin and dry eye, which limit effectiveness and therapeutic use. One approach to reduce the mechanism-based toxicity is to selectively target key tissues such as the liver. A known strategy is to utilize the liver-specific organic anion transporting polypeptides (OATPs), such as OATP1B1, OATP1B3, and/or OATP2B1, to facilitate liver uptake of the substrate drugs. Statins represent an excellent example for this approach. Most statins are substrates of OATPs and are taken up efficiently by liver via these transporters, minimizing the adverse effects of systemic exposure.117

Figure 20. SCD inhibitors disclosed by Pfizer. 5048



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Figure 21. SCD1 inhibitors reported by other organizations.

Merck Frosst. Given the adverse effects observed with systemically distributed SCD inhibitors, Merck Frosst scientists employed a liver-targeted approach to limit the compound exposure to eyes and skin with the intent to improve safety and tolerability. Utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs), Merck Frosst discovered a potent and liver-targeted SCD inhibitor compound 118 (MK-8245, Figure 122).118 Incorporating a tetrazolylacetic acid provided the recognition element for OATPs while maintaining the potency against SCD. Compound 118 was found to be a substrate of both OATP1B1 and 1B3. It had an IC50 of 3 nM against rat SCDl and 5 nM in human hepatocytes expressing OATP1. The activity against the non-OATP HepG2 cell line was much weaker with an IC50 of 1066 nM.118 The pharmacokinetic studies in mice, rats, and dogs showed that compound 118 was moderately bioavailable across species (F of 12%, 28%, and 40% in mice, rats, and dogs, respectively). Compound 118 was distributed to the liver, with low exposures in skin and harderian gland. The liver-to-skin ratios were >30:l in the species investigated.118 In preclinical evaluations in diet-induced obesity mouse models, compound 118 improved glucose clearance dose dependently with an ED50 of 7 mg/kg in an acute oral glucose tolerance test. In a 4week oral dosing study in a mouse diet-induced obesity model compound 118, at 20 or 60 mg/kg b.i.d., produced a modest prevention of body weight gain (∼5%) and reduction in hepatic steatosis, as confirmed by liver triglyceride levels. Food consumption in this study was not affected.118 Importantly, the liver-targeted compound 118 did not induce skin or eye adverse events during the 4-week treatment period at the 20 mg/kg dose. Consistently, there was significant reduction in liver DI (63%) while no significant reduction in harderian gland DI was detected, consistent with the exposure of compound 118 in these tissues ([liver] = 5 μM, [harderian gland] = 0.9 μM).118 To demonstrate improvement in whole body insulin sensitivity, a hyperinsulinemic−euglycemic glucose clamp experiment in overfed rats was carried out. Compound 118 dosed orally at 30 mg/kg b.i.d. significantly increased the glucose infusion rate required to maintain euglycemia, indicating improved insulin sensitivity. At a 2-fold higher dose (60 mg/kg b.i.d.) after dosing for 4 weeks, a clean skin and eyelid adverse event profile was observed.118 Compound 118 was advanced to phase IIa clinical trials for the treatment of

type 2 diabetes mellitus and inadequate glycemic control; however, the clinical studies appear to be terminated. Several other liver-targeted SCD inhibitors investigated by Merck Frosst are listed in Figure 22. These compounds are

Figure 22. Liver-targeted SCD1 inhibitors discovered by Merck Frosst.

potent SCD inhibitors with IC50 values in the nanomolar range that are reported to use OATP transporters and also demonstrated preferential distribution to liver.63,119−121 Schering. Schering discovered a series of benzo-fused spirocyclic oxazepine SCD1 inhibitors based on the HTS hit compound 124 (Figure 23) which had an IC50 of 6.4 μM

Figure 23. Liver targeting SCD1 inhibitors discovered by Schering Corporation.

against mSCD1.122−124 Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerated and allowed for tuning of potency and PK properties. Subsequent optimization efforts afforded potent compounds, such as compound 125, with favorable pharmacokinetic profiles. Compound 125 was highly potent with an mSCD1 5049



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impact of SCD1 therapy on all aspects of lipid metabolism. One further area for consideration is the identification of specific small patient populations characterized by increased SCD1 activity and/or altered lipid metabolism, which might show the same dramatic benefits of SCD1 inhibition as seen in the leptindeficient mice.12 It has been shown that highly potent inhibitors of SCD1 can be found across diverse scaffolds; therefore, barriers do not exist to identifying molecules with appropriate strong binding characteristics. However, there is less clarity about the optimal pharmacokinetic profile and the distribution to key target tissues to achieve efficacy with an effective therapeutic margin. Unfortunately, mechanism-based adverse effects in sensitive tissues, such as eye and skin, limit the utility of SCD1 inhibitors with high systemic exposure. Complicating matters further, studies in rodent knockout models suggest that targeting SCD1 deletion from adipose and/or liver is insufficient to elicit protection from obesity.125b Merck and others operated on the hypothesis that liver SCD1 inhibition was sufficient to elicit efficacy and directed their programs in that manner, specifically to avoid mechanismbased adverse effects. A series of publications describe the successful development of liver-targeted compounds; however, the Merck clinical program appears to have been halted after the early clinical investigations were completed. Reports suggest that safety was not an issue with their phase I study; thus, one could speculate that robust efficacy was not achieved with this tissue targeting approach. It is known that adipose tissue and muscle are also key players in SCD1 metabolic biology. Perhaps the impact of inhibiting SCD1 in these tissues is underestimated, and exposure in these metabolically relevant tissues is required. The importance of duration of inhibition likewise remains unclear, as many of the SCD1 inhibitors published have differing PK profiles. It has been assumed by many that 24 h suppression of SCD1 activity would be required; however, if the mechanisms driving efficacy involve predominantly de novo lipogenesis, perhaps timing is more critical than coverage. Because of the adverse skin and eye effects and narrow therapeutic margins of compounds with high systemic exposure and large volumes of distribution, managing the ideal timing and coverage along with required tissue distribution may be insurmountable. Thus, the early promise of this novel target for treating diabetes, obesity, and metabolic disorders may not come to fruition. Alternative Indications for SCD1 Inhibitors. The future utility of SCD1 inhibitors may lie beyond metabolic diseases in the areas of acne, skin disorders, and oncology. The feasibility of a topical SCD1 agent seems quite high. On the basis of the phenotype of the SCD1-deficient mice, it was evident that SCD1 has an important role in sebaceous gland function and skin health. The sebaceous gland is responsible for producing sebum, an oily or waxy secretion that lubricates and waterproofs the skin and hair of mammals. There are rare conditions that involve hyperactive sebaceous glands, which is also a feature of the more common condition of acne. Relative to healthy individuals, the sebaceous glands of acne patients are enlarged and produce more sebum, which then supports enhanced colonization by bacteria.126 There is a good correlation between reduced sebum production following retinoid therapy and reduced incidence of acne lesions.127 Therefore, it has been proposed that agents that reduce sebum production will be of interest for acne therapy. Recent publications provide the first evidence that small molecule

IC50 value of 8 nM and a favorable tissue distribution profile, with preferential liver exposure (liver/plasma ratio of 56 at 6 h). Compound 125 demonstrated a moderate reduction of the plasma desaturation index after a 4 h oral administration at 30 mg/kg; however, studies with higher doses over an extended period of dosing generated skin and eye side effects related to target inhibition.122 CV Therapeutics. As discussed earlier, CV Therapeutics also disclosed a liver targeting compound (compound 80, Figure 16). This compound preferentially distributed into liver (liver/ plasma ratio of 76 at 2 h after oral dosing of 5 mg/kg) and significantly reduced SCD activity in a dose-dependent manner in plasma and liver in a 5-day study in rats on a high sucrose diet.103 Xenon/Novartis. A series of thiazolylpyridinone compounds were disclosed by Xenon/Novartis in which some of the compounds were also preferentially distributed to liver.50b For example, compound 16 in Figure 6 demonstrated a liver to plasma ratio of 36 and a liver to eyelid ratio of 41 at 2 h after last dosing after 5 days of oral once daily dosing at 10 mg/ kg.50b This could be due to the acidic nature of the hydroxyl group of 4-hydroxypyridinone (pKa = 5).

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NEW PERSPECTIVES/FUTURE DIRECTIONS As shown above, extensive effort from a number of companies has resulted in many excellent SCD1 inhibitors with good in vitro activity and PD activity in rodent models. Furthermore, several examples of robust in vivo efficacy, including changes in body weight, plasma glucose, insulin sensitivity, and triglyceride levels, have been reported, albeit often accompanied with mechanism-based adverse effects. Despite this considerable volume of work, SCD1 inhibitors have not yet demonstrated clinical success or relevance in metabolic disease settings. According to available information at the time of writing this review, few SCD1 inhibitors had progressed to clinical studies, and there are no reports of compounds advancing beyond phase IIa. Although this is a disappointing outcome, there may be several explanations for the poor translation of preclinical PD and efficacy to clinical relevance. At the top of this list is the notorious difficulty of translating lipid metabolism from rodents to humans, as these species produce and process lipids in distinct manners. Differences in lipid handling and compensatory mechanisms in humans may necessitate longer durations of compound treatment to manifest effects, and the effects may be modest in comparison to rodents. Additionally, positive effects may be difficult to observe on top of existing standard of care treatment; thus, clinical design is critical. One potential solution to bridging the preclinical rodent data to the clinic would be to conduct efficacy studies in non-human primate models of disease. This may address two important pieces to the puzzle: diseased monkeys would have lipid handling systems very similar to patients, and the SCD5 isozyme would be present. It is not known what contribution SCD5 has to metabolic disease and whether activity against this enzyme would influence efficacy end points. There are a few studies indicating that SCD1 inhibition may work best in conjunction with other mechanisms to enhance efficacy and minimize side effects (Brown et al.).125a This paper reviews work showing that accumulation of saturated fatty acids can exacerbate inflammatory diseases and that these can be reduced or prevented by the coadministration of long chain essential fatty acids. This highlights the need to look at overall 5050



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Notes

SCD1 inhibition can reduce sebaceous gland size and number in animal models.39,113 The challenge in this arena is to optimize the properties and formulation for this indication. As so much of the research to date focused on systemic distribution or liver-targeting, the field of topical SCD1 inhibitors has yet to be explored. A further area ripe for exploration of therapeutic potential for SCD1 inhibitors is oncology. Recent publications have implicated SCD1 expression and activity in the pathogenesis of cancer.128,129 There is mounting evidence indicating a key role of SCD1 in the coordination of the intertwined pathways of lipid biosynthesis, energy sensing, and the transduction signals that influence mitogenesis and tumorigenesis, as well as the potential value of SCD1 as a target for novel pharmacological approaches in cancer therapy.128−147 Scaglia et al. have shown that SCD1 modulates not only the content of MUFA in cancer cells but also the overall process of lipogenesis.148 Remarkably, the ablation of SCD1 expression reduces cancer cell proliferation and in vitro invasiveness and dramatically impairs tumor formation and growth.130,148 They have also found that active SCD1 may be required for neoplastic cells to survive a lipotoxic stress, since SCD1 knockdown increases basal apoptosis and sensitizes the cells to the cytotoxic effects of excess SFA.148 Mauvoisin reported that low SCD1 expression is linked to a decrease in the proliferation rate of breast cancer cells. This was accompanied by an increase in GSK3 activity.133 Consequently, the nuclear translocation of β-catenin was decreased, and its transactivation capacity was decreased. This strongly suggests a role of SCD1 in epithelial to mesenchymal transition (EMT) and cancer progression. Therefore, SCD1 could be an efficient new therapeutic target for the treatment of metastatic breast cancer.133 Furthermore, a number of papers reported that SCD1 inhibitors slow tumor growth in xenograft models administered either alone131,132,142 or in combination with other chemotherapy.134 Thus, the potential value in the oncology field is just beginning to emerge. Oncology could be an ideal fit for a systemically distributed SCD1 inhibitor because of acute treatment paradigms and potentially reduced concerns with respect to skin and eye tolerability.

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The authors declare no competing financial interest. Biographies Zaihui Zhang is Senior Director, Medicinal Chemistry, at SignalChem Lifesciences Corporation. He received his Ph.D. from the University of British Columbia, Canada, under the supervision of Professor Chris Orvig. He conducted his postdoctoral research with Professor Leonard Wiebe in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta, Canada. He has over 2 decades of experience in the biotech industry during which he has successfully led a wide range of therapeutic programs across different disease areas. He was co-team leader of the SCD1 inhibitor project while working at Xenon Pharmaceuticals Inc. He currently leads the discovery and development of protein kinase inhibitors for next generation kinases to be used to treat cancer, inflammation, and neurological disorders. Natalie A. Dales, a Senior Investigator in Global Discovery Chemistry, has successfully led programs across many diseases in her tenure at Novartis Institutes for Biomedical Research. Currently, Natalie is working in Rare Diseases, bringing novel therapies forward in areas of high medical need. Natalie worked in the Cardiovascular and Metabolic Disease Area, where she worked primarily on lipid metabolism, hallmarked by the collaborative program between Novartis and Xenon on SCD1. Prior to working at NIBR, Natalie was a Senior Investigator at Millennium Pharmaceuticals, working on metabolic diseases and oncology programs, and an Investigator at Shionogi BioRearch. Natalie received her Bachelor of Science Degree from University of Michigan and her Ph.D. in Organic Chemistry from University of WisconsinMadison in 1997. Michael D. Winther has 3 decades of experience in the pharmaceutical industry, spanning vaccines, biologicals, and small molecules. He has been employed at Wellcome Research Laboratories (U.K.), Scotia Pharmaceuticals, The University of British Columbia, Canada, and Xenon Pharmaceuticals Inc., where he held several roles, including Senior Director of Research Operations. He established First Principles Consulting to provide consulting services to industrial and academic clients. He earned his Ph.D. from the University of Stirling, Scotland, under the supervision of Dr. Lewis Stevens in Biochemistry and conducted postdoctoral research with Professors Claudio Scazzhio and Wayne Davies at the University of Essex, U.K., in molecular biology and genetics. His interests include developing best practices to advance therapeutic products to fulfill unmet medical needs.

CONCLUSIONS AND FUTURE PROSPECTS

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In the early 2000s there was a rapid rise in research activity on SCD1 as a novel drug target, as evidenced by the number of patent submissions and publications describing potent, selective inhibitors. These efforts culminated in several in vivo active inhibitors, some of which entered the clinic. Limitations in the clinical utility from these efforts have led to the recognition that there were several important areas where there is a lack of fundamental knowledge regarding the role of SCD1 in regulating energy metabolism and lipid trafficking in humans. We have noted several of these knowledge gaps in this review, including the optimum tissue localization required for achieving efficacy and reduction of target-related adverse effects on eye and skin. It is possible that further investigation of the role of SCD5 will be helpful in fully exploiting this target. Finally, we point to future directions that appear feasible, even within the current framework of our understanding.

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ABBREVIATIONS USED SCD1, stearoyl-coenzyme A desaturase-1; D5D, Δ5 desaturase; D6D, Δ6 desaturase; C16:1n7, palmitoleic acid; C16:0, palmitic acid; C18:1n9, oleic acid; C18:0, stearic acid; HepG2, human hepatocellular carcinoma cell line; ip, intraperitoneal; SAR, structure−activity relationship; DI, desaturation index; VLDL, very low density lipoprotein; ASO, antisense oligonucleotides; FADH2, flavin adenine dinucleotide; NADPH, the reduced form of nicotinamide adenine dinucleotide phosphate; SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acids; HTS, high throughput screening; OATP, organic anion transporting polypeptide; DIO, diet induced obesity; b.i.d., twice a day; q.d., once a day

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AUTHOR INFORMATION

REFERENCES

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Corresponding Author

*Phone: 604-871-0321. E-mail: [email protected]. 5051



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