Department of Medicinal Chemistry, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Bioorg Med Chem Lett. 2010 Feb 15;20(4):1368-72. doi: 10.1016/j.bmcl.2010.01.012. Epub 2010 Jan 11.
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
基于已知的 CGRP 受体拮抗剂，构建了一个药效团模型，并利用该模型辅助鉴定新的先导化合物。设计、模拟和合成了包含替代“LHS”片段的类似物，这些片段通过酰胺或脲键与常见于 CGRP 受体拮抗剂中的“RHS”片段连接。结果，发现了一系列新型的噁二唑 CGRP 受体拮抗剂，并提出了随后的优化以提高其效力和生物利用度。
