title: 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.
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)-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=7.8 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 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: kenjirou.satou@takeda.com.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sato
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahagi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kubo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Hidaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamaura
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakariya
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Maki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Take
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Takekawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kitazaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice
chemical_list: D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase
keywords: Acyltransferase; CYP3A4; Indoline; MGAT2 inhibitor; Metabolic disease; Obesity; Phototoxicity; Time-dependent inhibition; Triacylglycerol