Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities

Sato, Kenjiro; Takahagi, Hiroki; Kubo, Ozora; Hidaka, Kousuke; Yoshikawa, Takeshi; Kamaura, Masahiro; Nakakariya, Masanori; Amano, Nobuyuki; Adachi, Ryutaro; Maki, Toshihide; Take, Kazumi; Takekawa, Shiro; Kitazaki, Tomoyuki; Maekawa, Taira

doi:10.1016/j.bmc.2015.06.003

Cited by 11 publications

(12 citation statements)

References 33 publications

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“…CpdB exhibited greater than 300-fold selectivity against related acyltransferases (DGAT1, DGAT2, and ACAT1). Those profiles were almost same as a previously reported MGAT2 inhibitor CpdA of which IC50 values for human and mouse MGAT2 were 7.8 and 2.4 nM, respectively [17].…”

Section: Resultssupporting

confidence: 89%

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

et al. 2020

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Monoacylglycerol O‐acyltransferase 2 (MGAT2) is one of the key enzymes responsible for triglyceride (TG) re‐synthesis in the small intestine. We have previously demonstrated that pharmacological inhibition of MGAT2 has beneficial effects on obesity and metabolic disorders in mice. Here, we further investigate the effects of MGAT2 inhibition on (a) fat‐induced gut peptide release and fat intake in normal mice and (b) metabolic disorders in high‐fat diet (HFD)‐fed ob/ob mice, a model of severe obesity and type 2 diabetes mellitus, using an orally bioavailable MGAT2 inhibitor Compound B (CpdB). CpdB inhibited elevation of plasma TG in mice challenged with an oil‐supplemented liquid meal. Oil challenge stimulated the secretion of two gut anorectic hormones (peptide tyrosine–tyrosine and glucagon‐like peptide‐1) into the bloodstream, and these responses were augmented in mice pretreated with CpdB. In a two‐choice test using an HFD and a low‐fat diet, CpdB selectively inhibited intake of the HFD in normal mice. Administration of CpdB to HFD‐fed ob/ob mice for 5 weeks suppressed food intake and body weight gain and inhibited elevation of glycated hemoglobin. These results indicate that pharmacological MGAT2 inhibition modulates fat‐induced gut peptide release and fat intake in normal mice and improves obesity and diabetes in HFD‐fed ob/ob mice and thus may have potential for development into a treatment of obesity and its related metabolic diseases.

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Section: Resultssupporting

confidence: 89%

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

et al. 2020

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“…Structure of compA was shown in Fig 1A . Synthesis of compA was reported previously [ 20 ]. This compound exhibited selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1) [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization

et al. 2016

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Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2-null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD-streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass-treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders.

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“…Compound 46 showeda ne xcellent ADMET profile and metabolic stabilitya sw ell as good bioavailability,t hus representing ap romising lead compound for the treatment of metabolic diseases. [161]…”

Section: Monoacylglycerol Acyltransferases (Mgats)mentioning

confidence: 99%

“…[160] in vitro (human MGAT2-expressingS f-9 cells) 31 MGAT2 46 7.8 nm ? [161] in vitro 32 ACAT1 K604 (47)450 nm competitive [ 168] in vitro 33 ACAT2 48 7.2 nm ? [169] in vitro (CHO cells) 34 FABP4 49 (K i = < 2nm)competitive [ 175] in vitro 35 FABP4 BMS309403 (50)( K i = < 2nm)competitive [ 175] characterized in vivo (rats) 36 CEPT To rcetrapib (27)39 nm reversible [123] in vivo (mice,m onkey,human) 37 CEPT Dalcetrapib (28)0.4-10 mm irreversible [127] in vivo (mice,m onkey,human) 38 CEPT Anacetrapib (29)46 nm ?…”

Section: Summary and Key Outstanding Questionsmentioning

confidence: 99%

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

et al. 2016

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The coordinated processes of lipid synthesis, degradation, and transport are mediated by enzymes, cofactors, and transport proteins. Accordingly, lipid-metabolizing enzymes represent logical targets for the treatment of dyslipidemia, a major risk factor for type 2 diabetes, atherosclerosis, and other disorders. Small-molecule tool compounds, modulating the functions of such proteins, can substantially facilitate the characterization of target proteins. Such molecules complement genetic studies, and allow time- and dose-dependent control of protein activity in biological systems. This can improve our understanding of physiological processes, give insights into the druggability of target proteins, and might finally result in the development of therapeutic compounds. In this review we summarize the current state of available inhibitors targeting key proteins in neutral lipid metabolism, with a focus on metabolic lipases, acyltransferases, and fatty-acid-binding proteins.

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Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities

Cited by 11 publications

References 33 publications

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

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