The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1
2012
Abstract We have systematically studied the effects of varying the central unnatural amino acid moiety on
CGRP receptorantagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23 , a potent
CGRP receptorantagonist with only weak
CYP3A4inhibition. Unlike the
triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3–1 mg/kg (sc), 23 showed robust inhibition of CGRP-induced increases in
marmosetfacial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1 H -
indazol-5-yl substituted alanine as a tyrosine surrogate.
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