Identification of Potent, Selective, and Metabolically Stable Peptide Antagonists to the Calcitonin Gene-Related Peptide (CGRP) Receptor

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• 作者：Les P. Miranda ; Jerry Ryan Holder ; Licheng Shi ; Brian Bennett ; Jennifer Aral ; Colin V. Gegg ; Marie Wright ; Kenneth Walker ; George Doellgast ; Rick Rogers ; Hongyan Li ; Violeta Valladares ; Kevin Salyers
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 25, 2008
• 年：2008
• 卷：51
• 期：24
• 页码：7889-7897
• 全文大小：232K
• 年卷期：v.51,no.24(December 25, 2008)
• ISSN：1520-4804

文摘

Calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that can be converted to a CGRP₁ receptor antagonist by the truncation of its first seven residues. CGRP(8−37), 1, has a CGRP₁ receptor K_i = 3.2 nM but is rapidly degraded in human plasma (t_1/2 = 20 min). As part of an effort to identify a prolonged in vivo circulating CGRP peptide antagonist, we found that the substitution of multiple residues in the CGRP peptide increased CGRP₁ receptor affinity >50-fold. Ac-Trp-[Arg²⁴,Lys²⁵,Asp³¹,Pro³⁴,Phe³⁵]CGRP(8−37)-NH₂, 5 (K_i = 0.06 nM) had the highest CGRP₁ receptor affinity. Using complimentary in vitro and in vivo metabolic studies, we iteratively identified degradation sites and prepared high affinity analogues with significantly improved plasma stability. Ac-Trp-[Cit^11,18,hArg²⁴,Lys²⁵,2-Nal^27,37,Asp³¹,Oic^29,34,Phe³⁵]CGRP(8−37)-NH₂, 32 (K_i = 3.3 nM), had significantly increased (>100-fold) stability over 1 or 5, with a cynomolgus monkey and human in vitro plasma half-life of 38 and 68 h, respectively.