Calcitonin Gene-Related Peptide Analogues with Aza and Indolizidinone Amino Acid Residues Reveal Conformational Requirements for Antagonist Activity at the Human Calcitonin Gene-Related Peptide 1 Rece

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• 作者：Damien Boeglin ; Fadi F. Hamdan ; Rosa E. Melendez ; J&eacute ; rô ; me Cluzeau ; Andre Laperriere ; Madeleine H&eacute ; roux ; Michel Bouvier ; William D. Lubell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：March 22, 2007
• 年：2007
• 卷：50
• 期：6
• 页码：1401 - 1408
• 全文大小：110K
• 年卷期：v.50,no.6(March 22, 2007)
• ISSN：1520-4804

文摘

Calcitonin gene-related peptide antagonists have potential for the treatment and prevention of disease statessuch as non-insulin-dependent diabetes mellitus, migraine headache, pain, and inflammation. To gain insightinto the spatial requirements for CGRP antagonism, three strategies were employed to restrict the conformationof the potent undecapeptide antagonist, [D³¹,P³⁴,F³⁵]CGRP_27-37. First, aza-amino acid scanning was performed,and ten aza-peptide analogues were synthesized and examined for biological activity. Second, (3S,6S,9S)-2-oxo-3-amino-indolizidin-2-one amino acid (I²aa) and (2S,6S,8S)-9-oxo-8-amino-indolizidin-9-one aminoacid (I⁹aa) both were introduced at positions 31-32, 32-33, 33-34, and 34-35, regions of the backboneexpected to adopt turns. Finally, the conformation of the backbone and side-chain of the C-terminal residue,Phe³⁵-Ala³⁶-Phe³⁷-NH₂, was explored employing (2S,4R,6R,8S)-9-oxo-8-amino-4-phenyl-indolizidin-9-oneamino acid (4-Ph-I⁹aa) as a constrained phenylalanine mimic. The structure-activity relationships exhibitedby our 26 analogues illustrate conformational requirements important for designing CGRP antagonists andhighlight the importance of -turns centered at Gly³³-Pro³⁴ for potency.