Synthesis of cinnamic acids and related isosteres as potent and selective alpha v beta 3 receptor antagonists.
We describe a series of conformationally-restricted cinnamic acid peptidomimetics as well as several cinnamic acid isosteres, including 3-phenylpropionic acids, 2-amino-3-phenylpropionic acids, phenoxyacetic acids and 2-phenylcyclopropylcarboxylic acids. Several analogues demonstrated low to sub-nanomolar potencies against alpha(v)beta(3) and greater than 200-fold selectivity against the other beta(3) integrin alpha(IIb)beta(3). In whole 293 cells, many of these analogues also showed modest selectivity against other alpha(v) integrins such as alpha(v)beta(1) and alpha(v)beta(5). These compounds were synthesized from readily available starting materials using either Heck or Mitsunobu coupling conditions.
Penning
Thomas D
TD
Department of Medicinal Chemistry, Pfizer Global Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.penning@abbott.com
Russell
Mark A
MA
Chen
Barbara B
BB
Chen
Helen Y
HY
Desai
Bipin N
BN
Docter
Stephen H
SH
Edwards
David J
DJ
Gesicki
Glen J
GJ
Liang
Chi-Dean
CD
Malecha
James W
JW
Yu
Stella S
SS
Engleman
V Wayne
VW
Freeman
Sandra K
SK
Hanneke
Melanie L
ML
Shannon
Kristen E
KE
Westlin
Marisa M
MM
Nickols
G Allen
GA
D002934:Cinnamates / Q000138:chemical synthesis* / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013237:Stereoisomerism
D002934:Cinnamates; D039302:Integrin alphaVbeta3; C029010:cinnamic acid