Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1369628 | Bioorganic & Medicinal Chemistry Letters | 2012 | 5 Pages |
Abstract
We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. 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 marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate.
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Xiaojun Han, Rita L. Civiello, Charles M. Conway, Deborah A. Cook, Carl D. Davis, Robert Macci, Sokhom S. Pin, Shelly X. Ren, Richard Schartman, Laura J. Signor, George Thalody, Kimberly A. Widmann, Cen Xu, Prasad V. Chaturvedula, John E. Macor,