title: Discovery of potent, cyclic calcitonin gene-related peptide receptor antagonists.
abstract: 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 nM 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 nM range.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Liang Zeng
authors.initials: LZ
authors.lastname: Yan
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.forename: Emily
authors.initials: E
authors.lastname: Rothstein
authors.forename: David
authors.initials: D
authors.lastname: Flora
authors.forename: Patrick
authors.initials: P
authors.lastname: Edwards
authors.forename: Baolin
authors.initials: B
authors.lastname: Li
authors.forename: Junqing
authors.initials: J
authors.lastname: Li
authors.forename: Renee
authors.initials: R
authors.lastname: Lynch
authors.forename: Renee
authors.initials: R
authors.lastname: Vaughn
authors.forename: Amy
authors.initials: A
authors.lastname: Clemens-Smith
authors.forename: Deborah
authors.initials: D
authors.lastname: McCarty
authors.forename: Charles
authors.initials: C
authors.lastname: Chow
authors.forename: Kevin L
authors.initials: KL
authors.lastname: McKnight
authors.forename: Jirong
authors.initials: J
authors.lastname: Lu
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: John P
authors.initials: JP
authors.lastname: Mayer
mesh_terms: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010455:Peptides