Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury.
Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
Huang
Adrian
A
Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
Moretto
Alessandro
A
Janz
Kristin
K
Lowe
Michael
M
Bedard
Patricia W
PW
Tam
Steve
S
Di
Li
L
Clerin
Valerie
V
Sushkova
Natalia
N
Tchernychev
Boris
B
Tsao
Desiree H H
DH
Keith
James C
JC
Shaw
Gray D
GD
Schaub
Robert G
RG
Wang
Qin
Q
Kaila
Neelu
N
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D002463:Cell Membrane Permeability; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D036904:Leukocyte Rolling / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D019007:P-Selectin / Q000037:antagonists & inhibitors*; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D020246:Venous Thrombosis / Q000188:drug therapy*
D006912:Hydroxyquinolines; D019007:P-Selectin; C528222:PSI-421; D012459:Salicylates