Departments of †Medicinal Chemistry, ‡Drug Discovery Biology, §Pharmacology, ∥Pharmacokinetics, and ⊥Structural Biology, Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
J Med Chem. 2014 Apr 24;57(8):3263-82. doi: 10.1021/jm401731q. Epub 2014 Apr 4.
Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
高通透性筛选（HTS）发现尼可酰胺 5 是一种有吸引力的受体激动剂起始点，随后对其进行了研究。经过全面的从苗头化合物到先导化合物的优化，发现了 45h，它是一种有效的、选择性的和可生物利用的 TGR5 激动剂，可用于临床前代谢疾病模型的测试。在遗传性肥胖小鼠（ob/ob）中，45h 在降低急性口服葡萄糖耐量试验（OGTT）中的峰值血糖水平方面与二肽基肽酶-4（DPP-4）抑制剂一样有效，但这种作用在慢性给药后消失。
