(MGAT2) Inhibitors for the Treatment of Metabolic Diseases and

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Perspective

Monoacylglycerol Acyltransferase 2 (MGAT2) Inhibitors for the Treatment of Metabolic Diseases and Nonalcoholic Steatohepatitis (NASH) Pratik Devasthale, and Dong Cheng J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b00864 • Publication Date (Web): 09 Jul 2018 Downloaded from http://pubs.acs.org on July 9, 2018

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Journal of Medicinal Chemistry

Monoacylglycerol Acyltransferase 2 (MGAT2) Inhibitors for the Treatment of Metabolic Diseases and Nonalcoholic Steatohepatitis (NASH)

Pratik Devasthale1,* and Dong Cheng2 Discovery Chemistry1 Discovery Biology2

Research and Development Bristol-Myers Squibb Company P. O. Box 4000, Princeton, NJ 08543-4000, United States

*Corresponding author. Phone: (609) 252-3304. Email: [email protected]

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ABSTRACT Monoacylglycerol transferase 2 (MGAT2) is a pivotal enzyme in the monoacylglycerol pathway for triacylglycerol synthesis. The pathway for triacylglycerol synthesis has provided several attractive targets for drug discovery in the treatment of metabolic diseases. Marketed drugs that inhibit enzymes in this pathway include orlistat (pancreatic lipase inhibitor), lomitapide (mitochondrial transfer protein inhibitor), and mipomersen (apolipoprotein B synthesis inhibitor) but poor gastrointestinal (GI) tolerability or safety considerations have limited their use and indications. In addition, several inhibitors of diacylglycerol transferase 1 (DGAT1) have advanced to the clinic but were withdrawn due to poor GI tolerability. This perspective first discusses the biological rationale in support of inhibition of MGAT2 as a therapeutic approach that may offer a distinct and superior efficacy versus GI tolerability profile, and then reviews advances in the discovery of small molecule MGAT2 inhibitors for the treatment of metabolic diseases and non-alcoholic steatohepatitis (NASH).

INTRODUCTION Monoacylglycerol acyltransferase 2 (MGAT2) has emerged as an attractive target for the treatment of obesity, type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH).1,2 In humans, MGAT2 is highly expressed in the small intestine and liver.3,4 MGAT2 knockout mice exhibit multiple healthy metabolic phenotypes, including decreased weight and adiposity, improved insulin sensitivity, decreased hepatic steatosis and increased energy expenditure in a high fat diet induced obese model. In addition, genetic deletion of MGAT2 leads to a delay of fat absorption towards the lower portion of the intestine that, in turn, increases 2


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the secretion of glucagon like peptide (GLP) 1 and peptide YY (PYY), gut hormones that are beneficial for glycemic control and are important for decreased appetite.1 This profile of delayed fat absorption and an increase of gut hormone secretion bears strong similarity to the mechanism observed in bariatric surgery, a clinically-proven effective way of treating obesity, diabetes and NASH.5,6 In the current Perspective, potential medical applications of MGAT2 inhibitors and its comparison with other targets in the same triacylglycerol synthesis pathway will be discussed. Then, a review of advances in the discovery of small molecule MGAT2 inhibitors and preclinical pharmacology summaries of selected MGAT2 inhibitor leads will be provided.

OBESITY AND TYPE 2 DIABETES MELLITUS (T2DM) It is estimated that 35% of all adults in the U.S. are obese (BMI > 30 kg/m2), resulting in an annual medical cost of around $147 billion in 2008.7 Obesity is a significant risk factor for many disorders, including T2DM, NASH, cardiovascular disease, and approximately 20% of all cancers.8-10 Data from the Diabetes Prevention Program illustrated that weight loss (7% in the first year) combined with increased physical activity (150 minutes of brisk walking per week) reduced the 4-year incidence of T2DM by 58% in adults with impaired glucose tolerance.11 In addition, significant weight loss (20%) resulting from gastric banding surgery in patients with T2DM resulted in an average reduction in glycosylated hemoglobin (HbA1c) of 1.6%.12 However, less than 3% of obese individuals are being treated with pharmacotherapy (phentermine, orlistat, lorcaserin, and phentermine/topiramate) due to concerns about the safety and efficacy of these drugs, along with biased attitudes about obesity as a disease.13,14 Neither 3



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lorcaserin nor phentermine/topiramate is marketed in Europe due to moderate weight loss efficacy and lack of long term clinical trials to rule out cardiovascular safety concerns. Unlike phentermine/topiramate, lorcaserin, and phentermine, the mechanism of action of orlistat is restricted to the GI tract, where it acts to block fat absorption by approximately 30%. Although it did not meet the FDA efficacy criteria for weight loss, it did prevent T2DM onset in obese adults with normal and impaired glucose tolerance at baseline over a period of four years, as shown in the ‘XENical in the prevention of Diabetes in Obese Subjects (XENDOS)’ study.15 Orlistat treatment also improved insulin sensitivity, along with reducing plasma free fatty acids and elevated the postprandial levels of the incretin, GLP-1.16 Unfortunately, one consequence of the mechanism of action for orlistat, which is to prevent the absorption of dietary fat, is the accumulation of lipid in the intestine. As a result, GI tolerability issues associated with orlistat have limited the use of this drug, suggesting a market for modulators of a drug target in the same pathway that elicits improved GI tolerability. Several other strategies to limit fat absorption have been explored including inhibition of microsomal triglyceride transfer protein (MTP)17 and inhibition of diacylglycerol acyltransferase 1 (DGAT1).18 Although significant weight loss was observed with both of these mechanisms, each mechanism was plagued with GI tolerability (diarrhea) and safety issues which have precluded advancement to the market as anti-obesity agents, although the MTP inhibitor, lomitapide, has been approved as a lipid-lowering agent for the treatment of homozygous familial hypercholesterolemia, a severe disease that results in early death.17

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Figure 1:

MGAT2 and intestinal fat absorption pathway.

Figure 1. MAG: monoacylglycerol; FA: fatty acid; DAG: diacylglycerol; TAG: triacylglycerol; MGAT: monoacylglycerol acyltransferase; DGAT: diacylglycerol acyltransferase; MTP: microsomal triglyceride transfer protein; ApoB: apolipoprotein B; CM: chylomicron.

MGAT2 inhibition offers an alternative method to attenuate triacylglycerol absorption. MGAT2 is highly expressed in the small intestine where it exerts an important role in the absorption of dietary fat in the monoacylglycerol triacylglycerol synthesis pathway (Figure 1). When dietary fat is ingested, pancreatic lipase digests triacylglycerol into free fatty acids and monoacylglycerol, which are absorbed by intestinal epithelial enterocytes. Once inside enterocytes, free fatty acids and monoacylglycerol are used as building blocks to resynthesize triacylglycerol by two sequential acylation steps: the first by MGAT and the second by DGAT, both enzymatic reactions. Triacylglycerols are then incorporated into chylomicrons and secreted into the lymph to be utilized as an energy supply for the body.19,20 Genetic deletion of MGAT2

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in mice or pharmacological treatment of mice with MGAT2 inhibitors appears to delay fat absorption to a more distal portion of the intestine and exhibits a suppressed plasma triacylglycerol excursion in response to a bolus of olive oil. These animals also demonstrate increased postprandial levels of GLP-1 and PYY in response to a chronic high fat diet regimen.21,22 The increased gut hormones may increase the satiety signal that may lead to decreased food intake and ultimately, weight loss. In contrast to pancreatic lipase (the target of orlistat) and DGAT1, which are essential for fat digestion and absorption in humans, MGAT2 is one component of a redundant intestinal lipid absorption system (Figure 1). In fact, despite its nomenclature, DGAT1 recognizes monoacylglycerol and catalyzes both MGAT and DGAT reactions.23 Further, monoacylglycerol acyltransferase 3 (MGAT3), present in higher species including humans, possesses dual MGAT/DGAT enzyme activity.24,25 The biochemical redundancy of the MGAT enzyme system suggests that selective MGAT2 inhibition will only partially attenuate triacylglycerol synthesis in the small intestine, resulting in a delay, rather than blockade of fat absorption. Hence, MGAT2 inhibition may mitigate the diarrhea side effect that is associated with other triacylglycerol/chylomicron synthesis targets in the intestine. Of importance, MGAT3 is only expressed in higher species, including humans, but it is a pseudo gene in rodents. The roles of MGAT2 in the dietary fat absorption and gut hormone regulation demonstrated in rodent models need to be confirmed in nonhuman primate models or in clinical trials.

NASH

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Parallel to the epidemic in obesity and T2DM, the prevalence of NASH is rising throughout the world. NASH has emerged as a major cause of end-stage liver disease and hepatocellular carcinoma (HCC) and is expected to overtake hepatitis C virus infection as the leading cause of demands for liver transplantation.26 Despite the high prevalence and medical consequences, there is no FDA-approved drug available for the treatment of NASH. An MGAT2 inhibitor could be used to treat NASH through the improvement of whole body metabolism, such as weight loss, since it is established that the degree of weight loss is associated with an improvement of NASH. In a retrospective study of biopsy-proven NASH patients who underwent lifestyle modification for weight loss, it was demonstrated that a greater proportion of patients with > 5% weight loss had NASH resolution and a 2-point reduction in Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) relative to those who had 10,000-fold) and DGAT1/2 (>15000-fold).49,50 In an OLTT using corn oil, a dose of 150 mg/kg of compound 11 effected a 68% decrease in TAG excursion 2 h after lipid loading relative to the difference in TAG levels seen between vehicle with and without the bolus corn oil administration. The free fraction concentrations of compound 11 at 2 h corresponded to 80-fold over its IC50. Since MGAT2 is primarily present in the enterocytes across the intestinal brush border, total inhibitor levels in the gut, rather than in the plasma, may conceivably drive MGAT2 inhibition, leading to reduced appearance of TAG in plasma in short duration OLTT studies. In analogous OLTT studies with a DGAT1 inhibitor, free Ctrough levels in the plasma at a dose that gave maximal efficacy were below its Ki.51 The authors thus suggested that intestinal compound exposures of DGAT1 inhibitors are more predictive of efficacy than plasma exposures. However, similar studies with MGAT2 inhibitors that address PK/PD correlations using gut vs. plasma exposures have not been reported. It is unclear though if given the high dose used in the OLTT (hence presumably high GI exposures) and low selectivity vs. MGAT3, the contribution of other acyltransferases present in the GI tract to the observed TAG-lowering efficacy is a possibility. Improvements in membrane permeability in this series were achieved without significantly increasing the lipophilicity of the compounds by substitution at the 9-position of the benzodiazepinone core, purportedly by H-bond donor modulation of the lactam NH.52 Within a series of 9-substituted analogs, a strong correlation between Caco-2 permeability and the strength of hydrogen-bond donating ability of the adjacent NH at N-1 was observed. X-ray crystal structures of 9-H vs. 9-Cl analogs indicated significant differences in crystal packing and intermolecular H-bonding interactions. Optimization of this series yielded compound 12, which demonstrated an improved developability profile with minimal liability risk for drug-drug 16


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interactions based on low CYP inhibition, low human Ether-à-go-go-Related Gene (hERG) channel inhibiton, low lipophilicity (log D7.4 = 1.9), acceptable plasma protein binding (1.7/3.0/3.7% free in human/rat/mouse, resp.), high crystalline solubility (150 µM), and high oral bioavailability (BA) in the mouse and rat (69% and 74%, respectively).

MGAT2 inhibitors from Eli Lilly

Substituted benzyl sulfonamides, exemplified by 13, 14, and 15, have been claimed as MGAT2 inhibitors by scientists at Eli Lilly.53-55 IC50 values for hMGAT2 inhibition in Caco-2 cells for 13, 14, and 15 were 58 nM, 274 nM, and 3.8 nM, respectively. OLTT data from beagle dogs was reported for several compounds. Compound 13 reduced TAG excursion by 69% at 10 mg/Kg and ~100% at a dose of 30 mg/kg in mice.

Representative MGAT2 inhibitors from Bristol-Myers Squibb

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6-Aryldihydropyridinone 16-1956-59 and 6-arylpyridinone 2060 compounds with potent hMGAT2 activity have been reported from our laboratories at Bristol-Myers Squibb. Substitutions at the C3 position included nitriles, amides, acylsulfonamides, tetrazoles, and tetrazolones. The S-stereochemistry at the C6-position of aryldihydropyridinones 16-19 gave greater potency for hMGAT2. Aryl or heteroaryl moeties with a small lipophilic substitutent were preferred at the 4-position of the dihydropyridinone or pyridinone.

MGAT2 inhibitors from Shionogi

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The spirocyclic dihydropyridinones 2161 and sulfonylmethylamides 2262 were claimed in the recent patent literature as potent hMGAT2 inhibitors. In the spirocyclic series, analogs with the 1,2,4-oxadiazol-5-one substituent showed greater potencies relative to ones with a tetrazole or a nitrile at the 3-position of the dihydropyridinone.61 Small lipophilic substituents on the phenyl ring of the spirobicyclic moeity were tolerated. In the series represented by 22, substitution of a 2-sulfonylacetamidomethyl at the 3-position of the dihydropyridinone yielded the most potent inhibitors.62 This substitution was more favorable than other variations such as amides, sulfonamides, ureas, and sulfonylureas. N-Phenylindolinesulfonamides from Takeda Pharmaceutical Sato et al have reported a series of N-phenylindoline-5-sulfonamides as potent, selective, and orally bioavailable MGAT2 inhibitors.63-66

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Compound 23 (MGAT2 IC50 = 130 nM), identified from high-throughput screening, was chosen as a starting point for optimization of potency, selectivity, and pharmacokinetic profiles. Initial SAR data suggested that the ArNHSO2Ar’ substructure was essential for MGAT2 activity; however, the introduction of a bicyclic central core and projection of lipophilic moieties from the dihydroindole nitrogen atom led to the discovery of 24. Compound 24 showed significant enhancements in MGAT2 inhibitory potency and selectivity over other acyltransferases. However, 24 suffered from poor metabolic stability in human and mouse liver microsomes, consistent with the high clearance and low oral bioavailability (4.6%) observed in mouse PK studies. Further SAR optimization, that included exploration of alternative bicyclic ring systems, including indazoles, benzimidazoles, benzoxazolones, as well as monocyclic scaffolds, culminated in the identification of 25. Compound 25 afforded the most optimal pharmacokinetic profile among the leads tested. At a dose of 1 mg/kg in mouse PK studies, an AUC0-8h of 842 ng.h/mL (1450 nM.h) and oral bioavailability of 52% was observed for 25. Compound 25 significantly inhibited TAG excursion, measured as a ratio of plasma chylomicrons and TAG, subsequent to an olive oil challenge in mice (oral fat tolerance test).63

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A structurally-related molecule 26 was extensively characterized in in vivo models of dyslipidemia, obesity, and diabetes.22 A meal tolerance test suggested a dose-dependent and long-lasting inhibitory effect on postprandial TAG excursion. At a dose of 30 mg/kg administered 16 h before the meal challenge, a 58% reduction in chylomicron TAG AUC was observed. Chylomicron TAG AUC represents TAG synthesized from dietary fat and was calculated by subtracting plasma TAG levels measured for each treated group from the untreated plasma TAG levels. Plasma levels of 26 at 24 h post-dose corresponded to a 1000-fold multiple over the mouse MGAT2 IC50. In a fasting, high fat diet, refeeding mouse model, a 59% reduction in food intake was observed after a single 30 mg/kg dose of 26. At a dose of 30 mg/kg/day, 26 demonstrated greater reductions in weight gain after 37 days than sibutramine. Reductions in body weight gain with 26 were associated with suppression of increases in fat mass, but not lean mass. Interestingly, in GLU-Tag enteroendocrine cells (a stable, immortalized differentiated murine cell line that expresses the proglucagon gene and secretes glucagon-like peptides in a regulated manner),67 GLP-1 secretion increased on treatment with monoacylglycerol but not diacyl- or triacyl-glycerol. This suggests that an MGAT2 inhibitor, which would increase levels of the monoacylglycerol substrates in the gut, are likely to increase 21



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GLP-1 secretion. Compound 26 was evaluated in a chronic, high fat diet-streptozotocin mouse model to assess anti-diabetic activity. While minimal effects on body weight, food intake, plasma and pancreatic insulin levels were observed in the study, improvements in HOMA-IR and peripheral insulin sensitivity were observed after 6 weeks of treatment with compound 26. Significant reductions in plasma and hepatic TAG levels and non-esterified fatty acids (NEFA) were observed. It was invoked by the authors that MGAT2 inhibition by treatment with 26 triggered structural remodeling in the upper part of the small intestine, as suggested by increases in the expression of genes involved in cholesterol synthesis and remodeling of the small intestine. Finally, intestinal phosphatidylcholine (PC) was reported to stimulate adverse gastrointestinal effects such as diarrhea, vomiting, and abdominal pain. These observations were consistent with the poor GI tolerability observed in the clinic with DGAT1 inhibitors which increase intestinal PC levels. Compound 26 was shown to significantly decrease intestinal PC levels and thus have the potential to provide a superior margin between efficacy and GI intolerability relative to DGAT1 inhibitors.

MGAT2 inhibitor lead from Japan Tobacco

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Compound 27 (JTP-103237) was reported by Japan Tobacco as an MGAT2 inhibitor (hMGAT2 IC50 = 19 nM) that modulated fat absorption and prevented diet-induced obesity under a high fat diet.68 Compound 27 was also shown to prevent fatty liver and suppress both TAG synthesis and lipogenesis.69 Compound 27 is selective for hMGAT2 over hDGAT2 (IC50 > 30 µM) and is 300-fold less potent at hMGAT3 relative to hMGAT2. MGAT2 inhibitory activity of 27 in microsomal S9 fractions from the small intestine, determined using [1-14C] oleoyl CoA as a substrate, was similar across human, rat, and mouse liver microsomes. Under high fat diet (35% fat), but not under low fat diet (3.1%) conditions, a significant decrease in food intake and body weight (BW) was observed in rats over 24 h, thus pointing to a dietary fatdependent satiety effect. This was corroborated under chronic conditions in a high fat, dietinduced obese mouse model with a significant reduction of >10% in BW increase and in food intake at doses of 30 mg/kg and above. In a high fat diet BDF1 mouse model, a strain that exhibits more impaired glucose tolerance than the C57Bl mouse, an improvement in glucose tolerance following an oral glucose tolerance test (OGTT) accompanied by significant decreases in fat weight and liver TAG were reported. In high fat-fed C576Bl mice, compound 27 increased O2 consumption in the early dark phase of a 24 h period. This suggests an association with changes in dietary fat absorption via intestinal MGAT2 inhibition. 23



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In a high sucrose, very low fat diet-fed mouse model of fatty liver, 27 reduced liver TAG content (not statistically significant at 100 mg/kg), reduced liver TAG, DAG and fatty acid synthesis, suggesting that de novo lipid synthesis was also decreased. Liver TAG content significantly correlated (r2 = 0.43) with MGAT2 inhibitory activity measured in liver S9 fractions. Additionally, decreases in plasma glucose, total cholesterol, and epididymal fat were observed. A 57% decrease in insulin levels at 30 mg/kg and a statistically non-significant 51% decrease at 100 mg/kg was observed. In a separate 21-day study at a dose of 100 mg/kg, a statistically significant 40% decrease in liver TAG was observed. Significant decreases in the expression of SREBP1c, SCD-1, and DGAT2 genes are consistent with inhibition of lipid synthesis in the liver. Finally, 27 showed no significant toxicities in rats after 2 weeks of treatment at doses of 100 and 1000 mg/kg. It has thus been suggested that inhibitory effects on fatty liver, TAG, and de novo lipogenesis may support targeting MGAT2 for the prevention of NAFLD, obesity, and diabetes in humans.

CONCLUSION The advances and learnings from the discovery and development of DGAT1 and pancreatic lipase inhibitors served as an instructive prequel to the identification of MGAT2 as a potentially more acceptable target for the treatment of obesity, metabolic diseases and NASH. Poor GI tolerability with orlistat has limited its use in the market while adverse GI effects at efficacious doses in clinical trials precluded the development of DGAT1 inhibitors. Our mechanistic understanding of the triacylglycerol synthesis, transport and absorption pathways outlined above suggests that, unlike a DGAT1 or pancreatic lipase inhibitor, an MGAT2 24


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inhibitor would be able to only partially block synthesis and appearance in plasma of triacylglycerol, thus potentially opening up a therapeutic window between efficacy and GI intolerability. Secondly, anti-obesity effects with MGAT2 inhibitors in rodents are purported to be a result of inhibition of intestinal MGAT2, thus offering a peripheral target that is likely to mitigate CNS side-effects associated with most anti-obesity agents. The large number of disclosures of potent and selective small-molecule MGAT2 inhibitors from a number of pharmaceutical companies in the past decade suggests an increasing level of interest in this target. Phase I clinical evaluation of these inhibitors is anticipated to provide an early read on pharmacodynamic biomarkers that relate to target engagement as well as safety and GI tolerability. A demonstration of a therapeutic window with an MGAT2 inhibitor from these studies would support its further clinical development. There is thus reason to remain optimistic about the potential of an MGAT2 inhibitor for treatment of metabolic diseases and NASH.

AUTHOR INFORMATION Corresponding author *Phone: (609) 252-3304. Email: [email protected]

Notes The authors declare the following competing financial interest(s): We are employees and shareholders of Bristol-Myers Squibb.

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Biographies Pratik Devasthale received his Ph. D. from the University of Kansas under the guidance of Prof. Lester Mitscher and conducted post-doctoral studies at University of Montreal in Prof. Stephen Hanessian’s laboratories before joining Bristol-Myers Squibb in 1997. He has been associated with the discovery of muraglitazar, a Phase III PPARα/γ dual agonist clinical candidate, and in advancing inhibitors of several other metabolic disease targets into clinical trials. He currently works as a Senior Principal Scientist in Oncology Discovery Chemistry. Dong Cheng received his Ph. D. in biochemistry from Dartmouth Medical School under the guidance of Dr. Ta-yuan Chang and conducted post-doctoral fellowship at the University of Texas, Southwestern Medical Center at Dallas where he was mentored by Drs. Michael Brown and Joseph Goldstein. In 2000, he joined DuPont Pharmaceuticals which became a part of Bristol-Myers Squibb in 2001. He has been the biology program leader for multiple drug discovery programs including several that advanced modulators of metabolic disease targets into clinical trials. Currently he works as a Senior Principal Scientist in Fibrosis Discovery Biology.

ACKNOWLEDGMENTS We thank Drs. Nicholas Meanwell and Bruce Ellsworth for their critical review of this manuscript, and Sachin Parelkar for the Table of Contents graphic

ABBREVIATIONS USED ApoB, apolipoprotein B; ASO, antisense oligonucleotide; BW, body weight; CB2, cannabinoid type 2; CM, chylomicron; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; FA, fatty acids; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; G-3-P, glycerol-3-phosphate; GPAT, 26


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glycerol-3-phosphate acyltransferase; HbA1c, glycosylated hemoglobin; HCC, hepatocellular carcinoma; HOMA-IR, homeostatic model assessment-insulin resistance; LPA, lysophosphatidic acid; LPAAT, lysophosphatidic acid acyltransferase; MAG, monoacylglycerol; MCD, methionine choline deficient; MGAT, monoacylglycerol acyltransferase; MTP, microsomal triglyceride transfer protein; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NEFA, non-esterified fatty acids; OGTT, oral glucose tolerance test; OLTT, oral lipid tolerance test; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PYY, peptide YY; SREBP, sterol regulatory element-binding protein; SCD-1, stearoyl-CoA desaturase-1; TAG, triacylglycerol; T2DM, Type II diabetes mellitus.

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(MGAT2) Inhibitors for the Treatment of Metabolic Diseases and

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