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.
Department of Medicinal Chemistry, Pfizer Global Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.penning@abbott.com
Thomas D
TD
Penning
Mark A
MA
Russell
Barbara B
BB
Chen
Helen Y
HY
Chen
Bipin N
BN
Desai
Stephen H
SH
Docter
David J
DJ
Edwards
Glen J
GJ
Gesicki
Chi-Dean
CD
Liang
James W
JW
Malecha
Stella S
SS
Yu
V Wayne
VW
Engleman
Sandra K
SK
Freeman
Melanie L
ML
Hanneke
Kristen E
KE
Shannon
Marisa M
MM
Westlin
G Allen
GA
Nickols
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