title: Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors.
abstract: Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced N-phenylindoline-5-sulfonamide derivative 10b, which displayed much improved potency, with an IC50 value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-1-carboxamide (24d) endowed with potent MGAT2 inhibitory activity (IC50 = 3.4 nM) and high oral bioavailability (F = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
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: 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: Shinji
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Takai
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: 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: 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: 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: Tsuyoshi
authors.initials: T
authors.lastname: Ishii
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: Taisuke
authors.initials: T
authors.lastname: Mochida
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: 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: Tomoyuki
authors.initials: T
authors.lastname: Kitazaki
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: C000599955:5-((2,4-difluorophenyl)sulfamoyl)-7-(2-oxopyrrolidin-1-yl)-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indole-1-carboxamide; D001562:Benzimidazoles; D001583:Benzoxazoles; D007191:Indazoles; D007211:Indoles; D013449:Sulfonamides; D014280:Triglycerides; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase