title: Synthesis and evaluation of cyclohexane carboxylic acid head group containing isoxazole and thiazole analogs as DGAT1 inhibitors.
abstract: Diacylglycerol acyltransferase 1 (DGAT1) is known to play an important catalytic role in the final step of triglyceride biosynthesis. High fat diet fed DGAT1 knockout mice were resistant to weight gain and exhibited increased insulin and leptin sensitivity thereby indicating a plausible role for DGAT1 inhibitors in the treatment of obesity. 4-Phenylpiperidine-1-carbonyl cyclohexanecarboxylic acid (compound 6, DGAT1 IC50 = 57 nM) has been lately reported as a potent DGAT1 inhibitor. In our search for newer scaffolds possessing potent DGAT1 activity we undertook a systematic diversification of compound 6 to identify a 4-(5-phenylthiazole-2-carboxamido)cyclohexanecarboxylic acid scaffold. Further linker optimization of this scaffold identified compound 9e (DGAT1 IC50 = 14.8 nM) as a potent DGAT1 inhibitor. Coupled with its in vitro potency, compound 9e also exhibited 112 percent plasma triglyceride reduction at a 3 mpk dose in an oral fat tolerance test (FTT) when studied in Swiss mice.
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India; Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Shivaji
authors.initials: S
authors.lastname: Kandre
authors.affiliation: Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Pundlik Rambhau
authors.initials: PR
authors.lastname: Bhagat
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: M Mahesh Kumar
authors.initials: MM
authors.lastname: Reddy
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Roda
authors.initials: R
authors.lastname: Dalal
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Amol
authors.initials: A
authors.lastname: Dixit
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Jessy
authors.initials: J
authors.lastname: Anthony
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Julie
authors.initials: J
authors.lastname: Bose
authors.affiliation: Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Raghuram
authors.initials: R
authors.lastname: Anupindi
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India. Electronic address: amolrgupte@gmail.com.
authors.forename: Amol
authors.initials: A
authors.lastname: Gupte
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007555:Isoxazoles / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D002264:Carboxylic Acids; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D013844:Thiazoles; C506365:Cyclohexane; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
keywords: Diacylglycerol acyltransferase (DGAT); Fat tolerance test (FTT); Obesity; Plasma triglycerides