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Discovery of potent, cyclic calcitonin gene‐related peptide receptor antagonists
Author(s) -
Yan Liang Zeng,
Johnson Kirk W.,
Rothstein Emily,
Flora David,
Edwards Patrick,
Li Baolin,
Li Junqing,
Lynch Renee,
Vaughn Renee,
ClemensSmith Amy,
McCarty Deborah,
Chow Charles,
McKnight Kevin L.,
Lu Jirong,
Nisenbaum Eric S,
Mayer John P.
Publication year - 2011
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1358
Subject(s) - calcitonin gene related peptide , agonist , chemistry , triptans , receptor , peptide , pharmacology , calcitonin , migraine , antagonist , calcitonin receptor , endocrinology , medicine , biochemistry , neuropeptide
Calcitonin gene‐related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side‐effects associated with the use of triptans. Our efforts to develop a novel, peptide‐based CGRP antagonist focused on the C‐terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C‐terminal CGRP (27–37) region identified a novel cyclic structure: Bz‐Val‐Tyr‐cyclo[Cys‐Thr‐Asp‐Val‐Gly‐Pro‐Phe‐Cys]‐Phe‐NH 2 (23) with a kb value of 0.126 n M against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05–0.10 n M range. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.