title: Novel acyl coenzyme A: diacylglycerol acyltransferase 1 inhibitors-synthesis and biological activities of N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides.
abstract: In a program to discover new small molecule diacylglycerol acyltransferase (DGAT)-1 inhibitors, screening of our in-house chemical library was carried out using recombinant human DGAT-1 enzyme. From this library, the lead compound 1a was identified as a new class of DGAT-1 inhibitor. A series of novel N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides 2 was designed from 1a, synthesized and evaluated for inhibitory activity against DGAT-1 enzyme. Among these compounds, N-(5-benzyl-4-phenyl-1,3-thiazol-2-yl)-4-(4,5-diethoxy-2-methylphenyl)-4-oxobutanamide 9 was found to exhibit potent inhibitory activity and good enzyme selectivities. Following administration in KKA(y) mice with 3 mg/kg high fat diet admixture for four weeks, 9 reduced body weight gain and white adipose tissue weight without affecting total food intake. These results suggested that the small molecule DGAT-1 inhibitor might have potential in the treatment of obesity and metabolic syndrome.
authors.affiliation: Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Co., Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Nakada_Yoshihisa@takeda.co.jp
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakada
authors.forename: Masaki
authors.initials: M
authors.lastname: Ogino
authors.forename: Kouhei
authors.initials: K
authors.lastname: Asano
authors.forename: Kazuko
authors.initials: K
authors.lastname: Aoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Minori
authors.initials: M
authors.lastname: Masago
authors.forename: Norikazu
authors.initials: N
authors.lastname: Tamura
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Shimada
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D054852:Small Molecule Libraries
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D051048:Diacylglycerol O-Acyltransferase