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

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 15; pp. 4544 - 4560
• Main Authors: Sato, Kenjiro, Takahagi, Hiroki, Kubo, Osamu, Hidaka, Kousuke, Yoshikawa, Takeshi, Kamaura, Masahiro, Nakakariya, Masanori, Amano, Nobuyuki, Adachi, Ryutaro, Maki, Toshiyuki, Take, Kazumi, Takekawa, Shiro, Kitazaki, Tomoyuki, Maekawa, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2015; Elsevier
• Subjects: Acyltransferase; Acyltransferases - antagonists & inhibitors; Animals; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CYP3A4; Cytochrome P-450 CYP3A - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Indoline; Life Sciences & Biomedicine; Metabolic disease; MGAT2 inhibitor; Mice; Obesity; Pharmacology & Pharmacy; Phototoxicity; Physical Sciences; Science & Technology; Time-dependent inhibition; Triacylglycerol; DIEA; LLE; DDI; HOMO; HLM; LUMO; LPL; ACAT; APCI; CYP3A4; MRT; MLM; Metabolic disease; Indoline; Triacylglycerol; Time-dependent inhibition; TDI; CYP; Obesity; dba; DMPK; ADME; MGAT2 inhibitor; DGAT; MGAT; CM; Acyltransferase; TEA; OFTT; TG; Phototoxicity; COENZYME; MGAT2 INHIBITORS; RISK; TRIGLYCERIDES; DEFICIENCY; DISCOVERY; CLONING; ANILINES; DISEASE; MICE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.06.003

A series of N-phenylindoline-5-sulfonamide derivatives was designed, synthesized, and evaluated as novel acyl CoA:monoacylglycerol acyltransferase-2 inhibitors for the treatment of obesity and metabolic disorders. [Display omitted] Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO–LUMO gap hypothesis during the course of optimization efforts.