Synthesis of 2,5-thiazole butanoic acids as potent and selective alpha(v)beta3 integrin receptor antagonists with improved oral pharmacokinetic properties.
We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs.
Wendt
John A
JA
Department of Medicinal Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. john.a.wendt@pfizer.com
Wu
Hongwei
H
Stenmark
Heather G
HG
Boys
Mark L
ML
Downs
Victoria L
VL
Penning
Thomas D
TD
Chen
Barbara B
BB
Wang
Yaping
Y
Duffin
Tiffany
T
Finn
Mary Beth
MB
Keene
Jeffery L
JL
Engleman
V Wayne
VW
Freeman
Sandra K
SK
Hanneke
Melanie L
ML
Shannon
Kristen E
KE
Nickols
Maureen A
MA
Steininger
Christina N
CN
Westlin
Marissa
M
Klover
Jon A
JA
Westlin
William
W
Nickols
G Allen
GA
Russell
Mark A
MA
D000284:Administration, Oral; D000818:Animals; D000951:Antigens, Neoplasm; D001682:Biological Availability; D002087:Butyrates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D000882:Haplorhini; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*
D000951:Antigens, Neoplasm; D002087:Butyrates; D039302:Integrin alphaVbeta3; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013844:Thiazoles; C073878:integrin alphavbeta6