Kandre Shivaji, Bhagat Pundlik Rambhau, Reddy M Mahesh Kumar, Dalal Roda, Dixit Amol, Deshmukh Nitin J, Anthony Jessy, Bose Julie, Anupindi Raghuram, Sharma Rajiv, Gupte Amol
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.
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India.
Eur J Med Chem. 2014 May 22;79:203-15. doi: 10.1016/j.ejmech.2014.03.077. Epub 2014 Mar 28.
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.
已知二酰甘油酰基转移酶1（DGAT1）在甘油三酯生物合成的最后一步中发挥重要的催化作用。高脂饮食喂养的DGAT1基因敲除小鼠对体重增加具有抗性，并且表现出胰岛素和瘦素敏感性增加，从而表明DGAT1抑制剂在肥胖症治疗中可能发挥作用。4-苯基哌啶-1-羰基环己烷羧酸（化合物6，DGAT1的半数抑制浓度IC50 = 57 nM）最近被报道为一种有效的DGAT1抑制剂。在寻找具有强大DGAT1活性的新型骨架的过程中，我们对化合物6进行了系统的多样化改造，以确定一种4-（5-苯基噻唑-2-甲酰胺基）环己烷羧酸骨架。对该骨架进行进一步的连接子优化后，确定化合物9e（DGAT1的IC50 = 14.8 nM）为一种有效的DGAT1抑制剂。在瑞士小鼠中进行口服脂肪耐量试验（FTT）时，化合物9e在3 mg/kg剂量下还表现出可使血浆甘油三酯降低112%，这与其体外活性相符。
