Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, RY50G-346, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2011 Jan 1;21(1):76-81. doi: 10.1016/j.bmcl.2010.11.074. Epub 2010 Nov 21.
A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.
现已发现一类新型 1,3,5-吡唑啉作为有效的人胰高血糖素受体拮抗剂。值得注意的是，化合物 26 在几种临床前物种中具有口服生物利用度，并对心脏离子通道、其他 B 族受体（如 hGIP 和 hGLP1）以及大量酶和其他受体具有选择性。当口服给予时，化合物 26 在恒河猴和转基因鼠药效模型中分别以 1 和 10mpk 的剂量有效抑制胰高血糖素引起的血浆葡萄糖波动。
