title: Evaluation of thiazole containing biaryl analogs as diacylglycerol acyltransferase 1 (DGAT1) inhibitors.
abstract: Biphenyl carboxylic acids, exemplified by compound 5, are known potent inhibitors of diacylglycerol acyltransferase, DGAT1, an enzyme involved in the final committed step of triglyceride biosynthesis. We have synthesized and evaluated 2-phenylthiazole, 4-phenylthiazole, and 5-phenylthiazole analogs as DGAT1 inhibitors. The 5-phenylthiazole series exhibited potent DGAT1 inhibition when evaluated using an in vitro enzymatic assay and an in vivo fat tolerance test in mice. Compound 33 (IC50 = 23 nM) exhibiting promising oral pharmacokinetic parameters (AUCinf = 7058 ng h/ml, T1/2 = 0.83 h) coupled with 87 percent reduction of plasma triglycerides in vivo may serve as a lead for developing newer anti-obesity agents.
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
authors.forename: Kishorkumar S
authors.initials: KS
authors.lastname: Kadam
authors.forename: Ravindra D
authors.initials: RD
authors.lastname: Jadhav
authors.forename: Shivaji
authors.initials: S
authors.lastname: Kandre
authors.forename: Tandra
authors.initials: T
authors.lastname: Guha
authors.forename: M Mahesh Kumar
authors.initials: MM
authors.lastname: Reddy
authors.forename: Manoja K
authors.initials: MK
authors.lastname: Brahma
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Amol
authors.initials: A
authors.lastname: Dixit
authors.forename: Lalit
authors.initials: L
authors.lastname: Doshi
authors.forename: Shaila
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Jayendra
authors.initials: J
authors.lastname: Devle
authors.forename: Anagha
authors.initials: A
authors.lastname: Damre
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
authors.forename: Amol
authors.initials: A
authors.lastname: Gupte
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; D014280:Triglycerides; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
keywords: 5-Phenylthiazole; Diacylglycerol acyltransferase (DGAT); Fat tolerance test; Obesity; Plasma triglycerides