Department of Molecular Sciences, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2012 Jul 15;22(14):4719-22. doi: 10.1016/j.bmcl.2012.05.118. Epub 2012 Jun 9.
We report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH(2) dipeptide amide C-terminus of the calcitonin gene-related peptide (CGRP). CGRP receptor antagonists containing these moieties displayed potent affinity, functional antagonism and excellent oxidative stability. Structure-activity relationship studies demonstrated the relative importance of hydrogen bond donor/acceptor functionalities and the preferred orientation of an aromatic ring. Antagonists showed potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries.
我们报告了刚性螺环系统的合成，这些系统是降钙素基因相关肽（CGRP）的丙氨酰-苯丙氨酰-氨（Ala-Phe-NH2）二肽酰胺 C 末端的构象限制变体。含有这些部分的 CGRP 受体拮抗剂具有很强的亲和力、功能拮抗作用和优异的氧化稳定性。构效关系研究表明氢键供体/受体功能和芳环的优选取向的相对重要性。拮抗剂表现出对 CGRP 诱导的离体人颅内动脉扩张的有效和完全逆转。
