title: Pharmacological characterization of a series of aryl-sulfonamide derivatives that potently and selectively inhibit monoacylglycerol acyltransferase 2.
abstract: Monoacylglycerol acyltransferase (MGAT) 2 is an endoplasmic reticulum membrane enzyme that catalyzes the synthesis of diacylglycerol (DAG) from fatty acyl-CoA and monoacylglycerol as substrates. It is important for the resynthesis of triacylglycerol in the intestine. We have identified a series of aryl-sulfonamide MGAT2 inhibitors and demonstrated pharmacological inhibition of MGAT2 improved hyperlipidemia, obesity, and diabetes in animal models. However, its mechanism of action has not been elucidated in molecular and cellular levels. In the present study, we have characterized a series of aryl-sulfonamide derivatives that potently and selectively inhibit human MGAT2 and determined their pharmacological profiles. Analyses on the molecular mechanism of a representative aryl-sulfonamide MGAT2 inhibitor revealed a reversible inhibitory activity and a binding activity to MGAT2. The aryl-sulfonamide derivatives exhibited potent inhibitory activities against both human and mouse intestinal MGAT activities, which were correlated to those determined using recombinant human and mouse MGAT enzymes. We have developed a cellular assay using Liquid Chromatography-Mass Spectrometry and confirmed that the aryl-sulfonamide derivatives suppressed DAG synthesis in the cellular context. We have thus elucidated their pharmacological profiles and provided the fundamental clues for understanding the molecular and cellular actions of the aryl-sulfonamide MGAT2 inhibitors.
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: ryutaro.adachi@takeda.com.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Satou
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sato
authors.affiliation: Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007422:Intestines / Q000201:enzymology; D051379:Mice; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase
keywords: Affinity Selection Mass Spectrometry; Cellular LC/MS assay; Compound B; Intestinal microsomes; Monoacylglycerol acyltransferase 2