Theberge Cory R, Bednar Rodney A, Bell Ian M, Corcoran Halea A, Fay John F, Hershey James C, Johnston Victor K, Kane Stefanie A, Mosser Scott, Salvatore Christopher A, Williams Theresa M, Zartman C Blair, Zhang Xu-Fang, Graham Samuel L, Vacca Joseph P
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 2008 Dec 1;18(23):6122-5. doi: 10.1016/j.bmcl.2008.10.019. Epub 2008 Oct 7.
The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.
先前公开的基于螺环乙内酰脲的降钙素基因相关肽（CGRP）受体拮抗剂通过对苯并咪唑酮取代基进行修饰来优化其效力。鉴定出的化合物在含有50%人血清的cAMP功能测定中显示出最小的变化。在恒河猴药效学试验中观察到这些化合物对CGRP介导的血管舒张具有阻断作用，并且体内效力与血清转移功能测定中的体外活性相关。
