Kim Ronald M, Chang Jiang, Lins Ashley R, Brady Ed, Candelore Mari R, Dallas-Yang Qing, Ding Victor, Dragovic Jasminka, Iliff Susan, Jiang Guoqiang, Mock Steven, Qureshi Sajjad, Saperstein Richard, Szalkowski Deborah, Tamvakopoulos Constantin, Tota Laurie, Wright Michael, Yang Xiaodong, Tata James R, Chapman Kevin, Zhang Bei B, Parmee Emma R
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2008 Jul 1;18(13):3701-5. doi: 10.1016/j.bmcl.2008.05.072. Epub 2008 May 22.
The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes.
本文描述了强效且选择性的氨基苯并咪唑类胰高血糖素受体拮抗剂的发现与优化过程。一种在多种临床前物种中具有适度药代动力学特性的化合物，在表达人胰高血糖素受体的转基因小鼠和恒河猴中，口服给药时能有效抑制胰高血糖素介导的血糖波动。该化合物在糖尿病小鼠模型中也能显著降低血糖水平。
