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. Issue 15 (1st August 2015)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 15(2015)
• Page Start: 4544
• Page End: 4560
• Publication Date: 2015-08-01
• Subjects: ACAT acyl CoA:cholesterol acyltransferase -- ADME absorption, distribution, metabolism and excretion -- APCI atomospheric pressure chemical ionization -- CM chylomicron -- dba dibenzylideneacetone -- CYP cytochrome P450 -- DDI drug–drug interaction -- DGAT acyl CoA:diacylglycerol acyltransferase -- DIEA N, N-diisopropylethylamine -- DMPK drug metabolism and pharmacokinetics -- HOMO highest occupied molecular orbital -- HLM human liver microsome -- LLE ligand lipophilicity efficiency -- LPL lipoprotein lipase -- LUMO lowest unoccupied molecular orbital -- MGAT acyl CoA:monoacylglycerol acyltransferase -- MLM mouse liver microsome -- MRT mean residence time -- OFTT oral fat tolerance test -- TEA triethylamine -- TDI time-dependent inhibition -- TG triacylglycerol; MGAT2 inhibitor -- Acyltransferase -- Triacylglycerol -- Obesity -- Metabolic disease -- Indoline -- Time-dependent inhibition -- CYP3A4 -- Phototoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.003
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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. Abstract: 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)-1 H -pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2, 3-dihydro-1 H -indole-5-sulfonamide (27c ) with potent MGAT2 inhibitory activity (IC50 = 7.8 nM) 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 3 mg/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.