2. Academic Validation
  3. Synthesis and evaluation of cyclohexane carboxylic acid head group containing isoxazole and thiazole analogs as DGAT1 inhibitors

Synthesis and evaluation of cyclohexane carboxylic acid head group containing isoxazole and thiazole analogs as DGAT1 inhibitors

  • Eur J Med Chem. 2014 May 22:79:203-15. doi: 10.1016/j.ejmech.2014.03.077.
Shivaji Kandre 1,  Pundlik Rambhau Bhagat 2,  M Mahesh Kumar Reddy 3,  Roda Dalal 3,  Amol Dixit 3,  Nitin J Deshmukh 3,  Jessy Anthony 3,  Julie Bose 3,  Raghuram Anupindi 3,  Rajiv Sharma 4,  Amol Gupte 5
Affiliations

Affiliations

  • 1 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.
  • 2 Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India.
  • 3 Department of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
  • 4 Department of Medicinal Chemistry, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India.
  • 5 Department of Medicinal Chemistry, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India. Electronic address: amolrgupte@gmail.com.
PMID: 24735646 DOI: 10.1016/j.ejmech.2014.03.077
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.

Keywords

Diacylglycerol acyltransferase (DGAT); Fat tolerance test (FTT); Obesity; Plasma triglycerides.

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