title: Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives.
abstract: A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.
authors.affiliation: Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company 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: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.forename: Yvan
authors.initials: Y
authors.lastname: Le Huerou
authors.forename: Timothy
authors.initials: T
authors.lastname: Turner
authors.forename: Scott A
authors.initials: SA
authors.lastname: Pratt
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Gonzales
authors.forename: Steve A
authors.initials: SA
authors.lastname: Boyd
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007313:Insecta; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D007202:Indicators and Reagents; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase