title: Peptide antagonists of the calcitonin gene-related peptide (CGRP) receptor with improved pharmacokinetics and pharmacodynamics.
abstract: Antagonism of the calcitonin gene-related peptide (CGRP) receptor may be a useful approach for migraine treatment. Selective PEGylated peptide antagonists to the CGRP receptor are described, derived from CGRP(8-37) with polymer derivatization at an engineered lysine-25 residue. Potent PEGylated peptides with improved pharmacokinetics were identified through peptide side-chain modification to mitigate metabolic liabilities. PEGylated Ac-Trp-[Cit(11,18),hArg(24),Lys(25),Asp(31),Pro(34),1-Nal(35)]CGRP(8-37)-NH2, 9, elicits a dose-dependent reduction of intradermal CGRP-induced local blood flow in rodents with an ED50 of 0.52 mg kg(-1) without any overt adverse effects.
authors.affiliation: Therapeutic Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320.
authors.forename: Les P
authors.initials: LP
authors.lastname: Miranda
authors.forename: Licheng
authors.initials: L
authors.lastname: Shi
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Holder
authors.forename: Marie
authors.initials: M
authors.lastname: Wright
authors.forename: Colin V
authors.initials: CV
authors.lastname: Gegg
authors.forename: Eileen
authors.initials: E
authors.lastname: Johnson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wild
authors.forename: Michael
authors.initials: M
authors.lastname: Stenkilsson
authors.forename: George
authors.initials: G
authors.lastname: Doellgast
authors.forename: Barton H
authors.initials: BH
authors.lastname: Manning
authors.forename: Kevin
authors.initials: K
authors.lastname: Salyers
mesh_terms: D015740:Calcitonin Gene-Related Peptide; D018015:Receptors, Calcitonin Gene-Related Peptide
chemical_list: D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide
keywords: antagonist; calcitonin gene-related peptide; metabolic stability; migraine; polyethylene glycol; structure-activity