title: Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes.
abstract: We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice.
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 305-333, Republic of Korea.
authors.forename: Suvarna H
authors.initials: SH
authors.lastname: Pagire
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 305-333, Republic of Korea.
authors.forename: Haushabhau S
authors.initials: HS
authors.lastname: Pagire
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Gwi Bin
authors.initials: GB
authors.lastname: Lee
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Seo-Jung
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kwak
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Jeong Im
authors.initials: JI
authors.lastname: Ryu
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.affiliation: Handok Pharmaceuticals Co., Ltd., Seoul 135-755, Republic of Korea.
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Handok Pharmaceuticals Co., Ltd., Seoul 135-755, Republic of Korea.
authors.forename: Dooseop
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea.
authors.forename: Duck Hyung
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 305-333, Republic of Korea. Electronic address: jhahn@krict.re.kr.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: D004791:Enzyme Inhibitors; C012698:adamantanecarboxylic acid; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D000218:Adamantane
keywords: Adamantane; DGAT1; Diabetes; Inhibitor; Obesity