Current Status of the Research and Development of Diacylglycerol O

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Current Status of the Research and Development of Diacylglycerol O‑Acyltransferase 1 (DGAT1) Inhibitors Miniperspective Robert J. DeVita*,‡ and Shirly Pinto† †

Department Cardiovascular and Diabetes Discovery, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States ‡ RJD Medicinal Chemistry and Drug Discovery Consulting, 332 W. Dudley Avenue, Westfield, New Jersey 07090, United States ABSTRACT: Diacylglycerol O-acyltransferase 1 (DGAT1) has recently become a highly interesting target for metabolic disorders as well as for hepatitis C virus (HCV). DGAT1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Pharmaceutical companies have developed many novel inhibitors of DGAT1, several of which have reached the clinic. Proof of target engagement was achieved with the observation of reduced triglycerides upon treatment of humans with DGAT1 inhibitors; however, there were gastrointestinal adverse events such as nausea, diarrhea, and vomiting. These adverse events have been reported with multiple compounds and are possibly linked to the target because of the recent identification of a human cohort deficient in DGAT1. Clinical studies are continuing in a trial to treat patients with an orphan indication for familial chylomicronemia. The full potential of DGAT1 as a therapeutic target will need to overcome observed clinical adverse events, which are possibly mechanism based. The widespread use of DGAT1 inhibitors will ultimately depend upon a better understanding of how to improve the GI tolerability of these agents.

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OVERVIEW AND INTRODUCTION This Miniperspective reviews the recent landscape of the discovery and clinical development of several DGAT1 small molecule inhibitors for the potential treatment of an array of metabolic disorders as well as recent biological insights that may provide the opportunity to treat hepatitis C virus (HCV). The authors have focused on the design and development of those small molecule inhibitors that have reached the clinic. Several recent reviews have appeared that have covered a variety of other structural classes of small molecule inhibitors and will not be discussed further here.1

regulation and the kinetics of fat absorption, with possible implications in gut hormone regulation. More recently, DGAT1 has been shown to be a key host factor for hepatitis C virus (HCV) infection by interacting with viral nucleocapsid core, which is required for the trafficking of core to lipid droplets.5 Overall, these data suggest that modulating the TG synthesis pathways via DGAT1 inhibition would have tremendous therapeutic potential in the treatment of such areas of unmet medical need as obesity, diabetes, dyslipidemia, hepatic steatosis, and HCV. Consistent with the phenotype of the DGAT1 KO, small molecule DGAT1 inhibitors of multiple chemical classes were demonstrated to lead to complete inhibition of postprandial plasma TG (PPTG) excursion after a lipid challenge. This robust effect was presented as the primary pharmacodynamics (PD) assay to guide structure−activity relationships (SAR).6 Moreover, in addition to the acute effect, chronic treatment of DGAT1 inhibitors has been shown to lead to improvement in metabolic parameters in several preclinical models. A lipophilic early benzazepinedione lead compound 1 (Figure 1) from Merck7 was demonstrated to lead to mechanism based weight loss after chronic dosing in DIO mice as well as prolongation of GLP-1 and PYY peptide release, attenuation of GIP, and delayed gastric emptying in response to a lipid challenge in dog

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BACKGROUND BIOLOGY Diacylglycerol O-acyltransferase 1 (DGAT1) is abundantly expressed in small intestine, liver, and adipose tissues and mediates the final step in triglyceride (TG) resynthesis during dietary fat absorption. The pharmaceutical industry has gained much interest in DGAT1 as a target for metabolic diseases following the report of the DGAT1 knockout (KO) mouse phenotype.2 DGAT1 KO mice show a host of beneficial metabolic phenotypes, most notably a reduction in the postprandial rise of plasma TG,2 resistance to diet induced obesity (DIO), and increased sensitivity for both insulin and leptin.3 Further characterization of the DGAT1 KO mouse demonstrated an increased and prolonged release of gut peptides, PYY, and GLP-1 as well as delayed gastric emptying.4 These findings suggest an important role for DGAT1 in the © XXXX American Chemical Society

Received: May 10, 2013

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Figure 1. Structures of DGAT1 inhibitors.

and mouse models.7 Chronic administration of a DGAT1 inhibitor to DIO mice led to weight loss, reduction in serum and liver triglycerides, and improvement in insulin sensitivity.8 Both these reports suggest an opportunity to develop clinical compounds to determine the effects of DGAT1 inhibition in humans for possible therapeutics effects in diabetes, cardiovascular, and obesity indications.

assays were used by the Pfizer team to fully characterize the biochemical mechanism of action which showed that 2 may bind competitively at the oleoly-CoA binding site. Murine in vivo studies showed that the compound had suitable oral bioavailability and upon chronic dosing in mice led to decreases in body weight (6.7%) accompanied by improved serum lipid profiles including reductions in TG and cholesterol. Minor effects on insulin secretion and excursion were also observed in separate oral glucose tolerance tests. Limited information is available on the fate of this molecule in preclinical or clinical studies.

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DESIGN AND DEVELOPMENT OF SMALL MOLECULE DGAT1 INHIBITORS THAT REACHED THE CLINIC In fact, the excitement around the target has led multiple pharmaceutical companies to initiate discovery programs in the pursuit of potent, selective, orally bioavailable DGAT1 inhibitors.1 The progress of these fruitful discovery efforts throughout the industry is evident by significant activity in the patent literature. Several of these companies have identified compounds that have been progressed into clinical studies and are described further.

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PFIZER Pfizer perceived concerns regarding the chemical and photochemical stability of the heterocyclic core in vivo of compound 2 as well as the potential for the carboxylic acid moiety to form acyl glucuronides. Thus, subsequent optimization focused on modification of the core structure and characterization of any potential acyl glucuronide metabolites, should the candidate molecules contain the ubiquitous carboxylic acid group. On the basis of several creative design concepts, the synthesis of novel compounds containing heterocycles with a carboxamide as part of the core substructure was completed. The carboxamide functional group was utilized to replace the arylimino group of 2, which was deduced to be the cause of the strongly UV absorptive properties of the original lead. The added steric projection of the carbonyl group in the resulting new design was not found to negatively affect potency, and indeed these new core structures did reduce the UV absorptive properties of the core structure, thus addressing any potential photochemical liability. The carbon-linked lactam molecule 3 had comparable potency; however, it was abandoned because of unsuitable metabolic stability as determined by in vitro studies.10 To address this liability, the new design featured the incorporation of an oxygen atom at a benzylic position in

JAPAN TOBACCO/TULARIK

An early report of a DGAT1 inhibitor came from a patent application resulting from a Japan Tobacco/Tularik collaboration9a from which 2 (T863) has since been characterized and utilized as a tool compound by the Pfizer group.9b This compound contains an aminopyrimidinoxazine heterocyclic core to which is appended a phenylcyclohexane acetic acid pharmacophore. The carboxylic acid moiety has been a standard structure feature on most subsequent DGAT1 inhibitor designs, since it adds solubility, improves pharmacokinetics and potency (vide infra), and has the potential to resolve some off target activities such as PXR induction and CYP inhibition profiles generally associated with lipophilic structural classes. In depth biochemical, functional cell based B

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DGAT2. The off target profile was also suitable for development with no concerns reported for hERG, CYP activity and only four off target binding activities of 10 mg but not at low doses of 2 and 5 mg, respectively).12 In another trial, 6 lowered triglycerides in familial chylomicronemia syndrome patients (a rare group of patients with high plasma TG) by 38.4% at the end of a 3-week dosing paradigm.20 Novartis has continued with a phase III study in this patient population, which is expected to be completed in late 2013, suggesting that the mechanism is validated for treatment of patients with hypertriglyceremia. No mention of GI AEs was made in this report, possibly because of the extremely low fat diet given to this specific patient population which was also indicated by the AstraZeneca report showing a possible correlation between meal fat content and GI AEs. The development of 6 is continuing as many other trials listed on clinicaltrials.gov are recruiting patients for studies of cardiovascular safety, patients with renal and hepatic impairment, and in combination with other TG lowering agents in spite of the potential for GI AEs. Interestingly, a study in HCV patients was prematurely terminated because of lack of efficacy, although GI adverse events were also observed in this trial where a higher fat meal was not included in the protocol.21

address through altered dosing paradigms. These studies designed to examine time of dosing relative to meal fasted vs fed were conducted. Additional studies that included variation in dosing paradigms (q.d. vs b.i.d.) and testing bioavailability of three different formulations, some of which included modified release using osmotic capsule, were reported. In early 2011, Pfizer initiated phase 1B, designed to assess the efficacy and safety of 4-week administration of 4 in T2DM subjects with insufficient glycemic control on metformin. A total of seven such studies are reported on clinicaltrial.gov,16 although not all data have been reported in the literature. AstraZeneca entered phase I in early 2010, and its primary indication appeared to be obesity. Three phase I clinical studies were completed with 5 tested at single and multiple doses. The last study was completed in August 2011 according to clinicaltrials.gov. The AstraZeneca team recently reported their results on one of these phase I ascending dose studies.17 The study enrolled 80 healthy male subjects to explore the safety, tolerability, pharmacokinetics, and pharmacological effects of DGAT1 inhibitor 5 across a dose range of 1−60 mg using a standardized mixed meal (SMM) containing 30%, 45%, or 60% fat content to assess the impact on triglyceride excursion. Compound 5 was rapidly absorbed with a Cmax at 1 h with a mean terminal half-life between 9 and 14 h. The exposure increased proportionally to the dose with no effect when the meal was given 4 h after dosing. There was an effect on Cmax (decrease) and Tmax (increase) when the meal was given within 30 min; however, overall oral bioavailability was not affected by the meal. The PD effects showed that TG area under the curve (AUC) increase was decreased by >75% compared to same individuals when given a 60% fat meal at doses of 5 mg or greater. No statistically significant effects on TG AUC were observed at lower fat meal of 45% at 5 and 20 mg doses, although a nonsignificant 50% decrease was observed at the higher dose. Analysis of the plasma correlation to PD effects showed EC50 = 0.44 μmol/L with a maximal effect of TG AUC decrease of 84% ± 9% compared to baseline. Further analysis of diacylglycerol (DG) in the plasma by mass spectrometry showed that there was no sign of DG accumulation. There were no overt safety concerns up to highest given dose of 5 with no cardiovascular adverse events reported, importantly including no changes in pulse, blood pressure, and ECG. There were, however, observations of GI adverse events (AEs) (nausea, diarrhea, and vomiting) that did limit the dose escalation in the study, with 43% of those dosed with the drug affected after pooling of the data. The investigators go on to disclose that there was a correlation to increased dose and increased fat content of the SMM on GI AEs. The authors contend that these results indicate a mechanism based gut effect of 5 resulting in decreases in TG after a high fat meal, thus proving the mechanism of DGAT1 inhibition in TG excursion across the gut wall. They go on to infer that the AEs may be the result of an accumulation of fatty acids in the intestinal lumen which could cause the nausea, vomiting, and diarrhea observed in humans, although it was not observed in preclinical species. It was also determined that the adverse events were reduced at lower dose and with lower fat content, showing that both have an impact. Some exploratory analyses of other plasma parameters disappointingly did not show effects on GLP-1 levels, which would be promising for any potential clinical effects on type II diabetic patients.18 A total of three

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DISCUSSION AND CONCLUSIONS The DGAT1 target has been extensively explored in preclinical models using both KO mouse experiments and small molecule tools to probe mechanism and efficacy in a variety of preclinical species. The inhibition or deletion of DGAT1 leads to a variety of interesting phenotypes, which propelled the excitement for the target to a high level of activity in the pharmaceutical industry. The potential for weight reduction for the treatment of obesity, effects on the GLP-1 incretin axis to impact glucose levels for the treatment of diabetes, and alteration of viral lipid trafficking for HCV treatment led to the development of extensive medicinal chemistry efforts. Subsequently, a series of heterocyclic inhibitors was reported that contained the important carboxylic acid pharmacophore initially identified by the Japan Tobacco/Tularik team. In general, these compounds possessed exciting profiles that included potency, preclinical efficacy, safety, and selectivity that allowed them to progress into clinical development. It may be inferred that subsequent IND-enabling studies did not reveal any liabilities to slow their progression into early stage phase I studies. Proof of mechanism was rapidly obtained by demonstrating reduction of TG excursion in DGAT1 inhibitor treated humans given a high fat meal. The overall results from these phase I studies, however, were extremely disappointing with respect to the appearance of strong GI AEs leading to nausea, diarrhea, and vomiting. These AEs were most pronounced when high fat meals were given with high doses of DGAT1 inhibitors, leading to presumed full inhibition of the enzyme both peripherally and in the GI tract. Interestingly, these AEs were not reported in any of the preclinical model studies. One can speculate that the inability of the human GI D

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tract to process the build-up of DG, fatty acids, and phospholipids in the lumen could be responsible for the poor tolerability of DGAT1 inhibition in humans. Indeed, a recent report of a human cohort (two patients) lacking DGAT1 resulted in a similar phenotype of poor GI tolerability, which resulted in the premature death of the first subject identified as DGAT1 deficient. The second patient survived after extensive diet modification and other treatments.22 The identification of this cohort clearly supported the concept that the gastrointestinal AEs associated with DGAT1 inhibition is likely to be on-target effects including downstream impact of the inhibition of TG processing in the GI tract. The authors explored the expression of DGAT1 and DGAT2 in murine and human intestinal tissue and found that mice expressed both enzymes while humans highly expressed only DGAT1. They go on to suggest that these expression profiles may account for the tolerability of DGAT1 inhibition in mice, while humans rely solely on DGAT1 for triglyceride processing in the GI tract, thus leading to the poor tolerability of DGAT1 inhibitors possibly due to a greater sensitivity on account of the lack of DGAT2 expression. Though the mechanism of the AEs is unclear, the authors also suggest that the accumulation of substrates, DG, and fatty acid or alternatively malabsorption of bile acids could be the cause of the diarrhea in humans. Subsequent clinical studies explored altered dosing regimens, controlled release, and other approaches to improve tolerability; however, no relief of these GI AEs has been reported to date. At lower fat loads or levels of inhibition, the effects of the DGAT1 inhibitors produced unimpressive decreases in serum TGs with the concomitant nonsignificant increases in GLP1 deemed not useful for treatment of diabetes. The accumulation of these negative data resulted in the abandonment of the clinical programs from the majority of companies pursuing DGAT1 inhibitors. Novartis continues in an orphan indication for familial chylomicronemia as well as in a few other esoteric patient populations as reported on clinicaltrial.gov. The outcomes of these trials are highly anticipated to determine whether an approvable indication for 6 will be possible as well to gain a greater understanding of tolerability in these specific patient populations. The identification of one individual homozygous for DGAT1 deficiency, apparently healthy at 3 years of age, suggests that total DGAT1 deficiency is tolerable, however it remains in question as to whether broader indications for DGAT1 inhibitors will be possible without the ability to attenuate the poor tolerability of these drugs in humans.

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porters, GPCRs, and enzymes, including DGAT1 as co-lead of the Merck program team. He has served on the Long Range Planning Committee of the ACS Medicinal Chemistry Division and the scientific organizing committee of the EFMC Frontiers of Medicinal Chemistry series of meetings. Shirly Pinto is currently a director in the Cardiovascular and Diabetes group at Merck & Co., Inc. She joined Merck in January 2005 after a postdoctoral appointment with Dr. Jeffrey Friedman at Rockefeller University, where she investigated neuronal plasticity and hypothalamic rewiring of genetically obese mice. She received her Ph.D. from Cornell Medical School/Cold Springs Laboratory where she was awarded the Rachele Prize for a graduating Ph.D. student with the best published work. Since joining Merck, Dr. Pinto has had a major impact on new target identification and validation, co-leading several lead optimization programs related to diabetes, obesity, and atherosclerosis including DGAT1.

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ACKNOWLEDGMENTS We thank Tim Cernak for assistance in preparing the structures for the manuscript. ABBREVIATIONS USED ACAT, acetyl-coA cholesterol acyltransferase; AUC, area under the curve; DG, diacylglycerol; DGAT1, diacylglycerol Oacyltransferase 1; IND, investigatory new drug; KO, knockout; PPTG, postprandial triglyceride; PD, pharmacodynamics; PYY, peptide YY; PK, pharmacokinetics; SMM, standardized mixed meal; SAR, structure−activity relationship; TE, target engagement; TG, triglyceride

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REFERENCES

(1) (a) Dow, R. L. Acyl-CoA: Diacylglycerol Acyl Transferase 1 Inhibition as an Approach to the Treatment of Type II Diabetes. In New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches; Jones, R. M., Ed.; Royal Society of Chemistry Publishing: Cambridge, U.K., 2012; pp 215−248. (b) Birch, A. M.; Buckett, L. K.; Turnbull, A. V. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr. Opin. Drug Discovery Dev. 2010, 13, 489−496. (c) Matsuda, D.; Tomoda, H. DGAT inhibitors for obesity. Curr. Opin. Invest. Drugs 2007, 8, 836−841. (2) Smith, S. J.; Cases, S.; Jensen, D. R.; Chen, H. C.; Sande, E.; Tow, B.; Sanan, D. A.; Raber, J.; Eckel, R. H.; Farese, R. V., Jr. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT. Nat. Genet. 2000, 25, 87−90. (3) Chen, H. C.; Smith, S. J.; Ladha, Z.; Jensen, D. R.; Ferreira, L. D.; Pulawa, L. K.; McGuire, J. G.; Pitas, R. E.; Eckel, R. H.; Farese, R. V., Jr. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J. Clin. Invest. 2002, 109, 1049− 1055. (4) Okawa, M.; Fujii, K.; Ohbuchi, K.; Okumoto, M.; Aragane, K.; Sato, H.; Tamai, Y.; Seo, T.; Itoh, Y.; Yoshimoto, R. Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion. Biochem. Biophys. Res. Commun. 2009, 390, 377−381. (5) Herker, E.; Harris, C.; Hernandez, C.; Carpentier, A.; Kaehlcke, K.; Rosenberg, A. R.; Farese, R. V., Jr.; Ott, M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat. Med. 2010, 16, 1295−1298. (6) Birch, A. M.; Birtles, S.; Buckett, L. K.; Kemmitt, P. D.; Smith, G. J.; Smith, T. J.; Turnbull, A. V.; Wang, S. J. Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase1inhibitors. J. Med. Chem. 2009, 52, 1558−1568. (7) Liu, J.; Gorski, J.; Gold, S. J.; Chen, D.; Chen, S.; Forrest, G.; Itoh, Y.; Marsh, D. J.; McLaren, D. J.; Shen, Z.; Sonatore, L.; CarballoJane, E.; Craw, S.; Guan, X.; Karanam, B.; Sakaki, J.; Szeto, D.; Tong,

AUTHOR INFORMATION

Corresponding Author

*Telephone: 1-908-456-0772. E-mail: Robert_devita@verizon. net. Notes

The authors declare no competing financial interest. Biographies Robert J. DeVita is the principal and owner of RJD Medicinal Chemistry and Drug Discovery Consulting, LLC in Westfield, NJ. He has worked for many years in the pharmaceutical industry at Merck in Rahway, NJ, and in biotechnology prior to starting a consulting practice serving clients on the East and West Coast. He has experience in a variety of therapeutic areas, collaborating with and leading teams that have delivered clinical compounds in metabolic, CNS, cardiovascular, pain, and oncology indications that targeted transE

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X.; Xiao, J.; Yoshimoto, R.; Yu, H.; Balkovec, J.; Pinto, S. Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide releasepotential insight into mechanism of action. Obesity 2013, 21, 1406−1415. (8) Maciejewski, B. S.; LaPerle, J. L.; Chen, D.; Ghosh, A.; Zavadoski, W. J.; McDonald, T. S.; Manion, T. B.; Mather, D.; Patterson, T. A.; Hanna, M.; Watkins, S.; Gibbs, E. M.; Calle, R. A.; Steppan, C. M. Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans. Am. J. Physiol.: Gastrointest. Liver Physiol. 2013, 304, G958−G969. (9) (a) Fox, B. M.; Furukawa, N.; Hao, X.; Iio, K.; Inaba, T.; Jackson, S. M.; Kayser, F.; Labelle, M.; Li, K.; Matsui, T.; McMinn, D. L.; Ogawa, N.; Rubenstein, S. M.; Sagawa, S.; Sugimoto, K.; Suzuki, M.; Tanaka, M.; Ye, G.; Yoshida, A.; Zhang, J. WO2004/047755A2, 2004; U.S. Patent Application US 2004/0209871 A1, 2004. (b) Cao, J.; Zhou, Y.; Peng, H.; Huang, X.; Stahler, S.; Suri, V.; Qadri, A.; Gareski, T.; Jones, J.; Hahm, S.; Perreault, M.; McKew, J.; Shi, M.; Xu, X.; Tobin, J. F.; Gimeno, R. E. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J. Biol. Chem. 2011, 286, 41838− 41851. (10) Dow, R. L.; Li, J. C.; Pence, M. P.; Gibbs, E. M.; LaPerle, J. L.; Litchfield, J.; Piotrowski, D. W.; Munchhof, M. J.; Manion, T. B.; Zavadoski, W. J.; Walker, G. S.; McPherson, R. K.; Tapley, S.; Sugarman, E.; Guzman-Perez, A.; DaSilva-Jardine, P. Discovery of PF04620110, a potent, selective, and orally bioavailable inhibitor of DGAT1. ACS Med. Chem. Lett. 2011, 2, 407−412. (11) (a) Barlind, J. G.; Bauer, U. A.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Davies, R. D. M.; Eriksson, J. W.; Hammond, C. D.; Hovland, R.; Johannesson, P.; Johanson, M. J.; Kemmitt, P. D.; Lindmark, B. T.; Morentin Gutierrez, P.; Noeske, T. A.; Nordin, A.; O’Donnell, C. J.; Petersson, A. U.; Redzic, A.; Turnbull, A,V.; Vinblad, J. Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687). J. Med. Chem. 2012, 55, 10610−10629. (b) McCoull, W.; Addie, M. S.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Bowker, S. S.; Boyd, S.; Chapman, S.; Davies, R. D. M.; Donald, C. S.; Green, C. P.; Jenner, C.; Kemmitt, P. D.; Leach, A. G.; Moody, G. C.; Morentin Gutierrez, P.; Newcombe, N. J.; Nowak, T.; Packer, M. J.; Plowright, A. T.; Revill, J.; Schofield, P.; Sheldon, C.; Stokes, S.; Turnbull, A. V.; Wang, S. J. Y.; Whalley, D. P.; Wood, J. M. Identification, optimization and in vivo evaluation of oxadiazole DGAT1 inhibitors for the treatment of obesity and diabetes. Bioorg. Med. Chem. Lett. 2012, 22, 3873−3878. (12) Serrano-Wu, M. H.; Kwak, Y.; Coppola, G.; Foster, C.; Gilmore, T.; Gong, Y.; He, G.; Hou, Y.; Kantor, A.; Li, J.; Mergo, W.; Nakajima, K.; Neubert, A.; Radetich, B.; Stroup, B.; Sung, M.; Szklennik, P.; Tichkule, R.; Yang, L.; Yoon, T.; Zhu, Y.; Wareing, J.; Hosagrahara, V.; Jain, M.; Chatelain, R.; Commerford, R.; Dardik, B.; Meyers, D.; Hubbard, B. Discovery of a DGAT1 Inhibitor with Robust Suppression of Postprandial Triglyceride Levels in Humans. Presented at the 243rd National Meeting of the American Chemical Society, San Diego, CA, March 26, 2012; Session “Diacylglycerol Acyltransferase 1 (DGAT1) and Metabolic Diseases”, MEDI 230. (13) Serrano-Wu, M. H.; Coppola, G.; Gong, Y.; Neubert, A.; Chatelain, R.; Clairmont, K. B.; Commerford, R.; Cosker, T.; Daniels, T.; Hou, Y.; Jain, M.; Juedes, M.; Li, L.; Mullarkey, T.; Rocheford, E.; Sung, M. J.; Tyler, A.; Yang, Q.; Yoon, T.; Hubbard, B. K. Intestinally targeted diacylglycerol acyltransferase 1 (DGAT1) inhibitors robustly suppress postprandial triglycerides. ACS Med. Chem. Lett. 2012, 3, 411−415. (14) Hagmann, W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008, 51, 4359−4369. (15) Serrano-Wu, M. H. Manuscripts describing the design and SAR of LCQ908 are in preparation; unpublished results. (16) ClinicalTrials.gov for PF-04620110. http://clinicaltrials.gov/ ct2/results?term=PF-04620110&Search=Search.

(17) Denison, H.; Nilsson, C.; Kujacic, M.; Lofgren, L.; Karlsson, C.; Knutsson, M.; Eriksson, J. W. Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single dose study. Diabetes, Obes. Metab. 2013, 15, 136−143. (18) Drucker, D. J. Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes. Curr. Pharm. Des. 2001, 7, 1399−1412. (19) Novartis. Clinical Trial Results Database. http://www.novctrd. com/ctrdWebApp/clinicaltrialrepository/displayFile.do?trialResult= 4314. (20) Meyers, C.; Gaudet, D.; Tremblay, K.; Amer, A.; Chen, J.; Aimin, F. The DGAT1 inhibitor LCQ908 decreases triglyceride levels in patients with the familial chylomicronemia syndrome. J. Clin. Lipidol. 2012, 6, 266−267. (21) Novartis Clinical Trial Results Database. http://www.novctrd. com/ctrdWebApp/clinicaltrialrepository/displayFile.do?trialResult= 8064. (22) Haas, J. T.; Winter, H. S.; Lim, E.; Kirby, A.; Blumenstiel, B.; DeFelice, M.; Gabriel, S.; Jalas, C.; Branski, D.; Grueter, C. A.; Toporovski, M. S.; Walther, T. C.; Daly, M. J.; Farese, R. V., Jr. DGAT1 mutation is linked to a congenital diarrheal disorder. J. Clin. Invest. 2012, 122, 4680−4684.

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