The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1.

Autor: Han X; Department of Molecular Sciences and Candidate Optimization (MSCO), Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiaojun.han@bms.com, Civiello RL, Conway CM, Cook DA, Davis CD, Macci R, Pin SS, Ren SX, Schartman R, Signor LJ, Thalody G, Widmann KA, Xu C, Chaturvedula PV, Macor JE, Dubowchik GM
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Jul 15; Vol. 22 (14), pp. 4723-7. Date of Electronic Publication: 2012 Jun 01.
DOI: 10.1016/j.bmcl.2012.05.074
Abstrakt: 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 (s.c.), 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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