The discovery of highly potent CGRP receptor antagonists
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- 作者：Craig A. Stump ; Ian M. Bell ; Rodney A. Bednar ; Joseph G. Bruno ; John F. Fay ; Steven N. Gallicchio ; Victor K. Johnston ; Eric L. Moore ; Scott D. Mosser ; Amy G. Quigley ; Christopher A. Salvatore ; Cory R.
- 关键词：CGRP ; Migraine ; Headache
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2009
- 出版时间：1 January 2009
- 年：2009
- 卷：19
- 期：1
- 页码：214-217
- 全文大小：183 K
文摘
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP Ki = 40 pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.