高效降钙素基因相关肽（CGRP）受体拮抗剂的发现。
The discovery of highly potent CGRP receptor antagonists.
作者信息
Stump Craig A, Bell Ian M, Bednar Rodney A, Bruno Joseph G, Fay John F, Gallicchio Steven N, Johnston Victor K, Moore Eric L, Mosser Scott D, Quigley Amy G, Salvatore Christopher A, Theberge Cory R, Blair Zartman C, Zhang Xu-Fang, Kane Stefanie A, Graham Samuel L, Vacca Joseph P, Williams Theresa M
机构信息
Department of Medicinal Chemistry, Merck & Co, Inc, West Point, PA 19486, USA.
出版信息
Bioorg Med Chem Lett. 2009 Jan 1;19(1):214-7. doi: 10.1016/j.bmcl.2008.10.106. Epub 2008 Oct 31.
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 K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
对先前确定的螺环乙内酰脲先导结构进行合理修饰，已鉴定出一系列有效的螺环氮杂氧化吲哚CGRP受体拮抗剂。发现氮杂氧化吲哚是乙内酰脲的通用替代物，能持续提高体外活性。茚满基螺环氮杂氧化吲哚与优化的苯并咪唑啉酮的组合产生了高效拮抗剂（例如，25，CGRP K(i)=40pM）。密切相关的化合物27在犬和恒河猴中显示出良好的口服生物利用度。
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