The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1.
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.
Department of Molecular Sciences and Candidate Optimization (MSCO), Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiaojun.han@bms.com
Xiaojun
X
Han
Rita L
RL
Civiello
Charles M
CM
Conway
Deborah A
DA
Cook
Carl D
CD
Davis
Robert
R
Macci
Sokhom S
SS
Pin
Shelly X
SX
Ren
Richard
R
Schartman
Laura J
LJ
Signor
George
G
Thalody
Kimberly A
KA
Widmann
Cen
C
Xu
Prasad V
PV
Chaturvedula
John E
JE
Macor
Gene M
GM
Dubowchik
D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002144:Callithrix; D003331:Coronary Vessels / Q000187:drug effects; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D065692:Cytochrome P-450 CYP3A Inhibitors; D014443:Tyrosine