Bell Ian M, Bednar Rodney A, Fay John F, Gallicchio Steven N, Hochman Jerome H, McMasters Daniel R, Miller-Stein Cynthia, Moore Eric L, Mosser Scott D, Pudvah Nicole T, Quigley Amy G, Salvatore Christopher A, Stump Craig A, Theberge Cory R, Wong Bradley K, Zartman C Blair, Zhang Xu-Fang, Kane Stefanie A, Graham Samuel L, Vacca Joseph P, Williams Theresa M
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 2006 Dec 15;16(24):6165-9. doi: 10.1016/j.bmcl.2006.09.045. Epub 2006 Oct 5.
A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K(i)=21nM) with good oral bioavailability in three species.
一种用于鉴定基于螺环乙内酰脲的降钙素基因相关肽（CGRP）拮抗剂的快速类似物方法提供了新型的低分子量先导化合物。对这些先导化合物进行修饰得到了一系列基于苯并咪唑啉酮的纳摩尔级CGRP受体拮抗剂。这些拮抗剂的口服生物利用度与极性表面积呈负相关，这表明膜通透性是吸收的关键限制因素。经过优化得到了化合物12，它是一种强效的CGRP受体拮抗剂（K(i)=21nM），在三种物种中都具有良好的口服生物利用度。
