title: 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.
abstract: 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.
authors: Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
authors: Adrian
authors: A
authors: Huang
authors: Alessandro
authors: A
authors: Moretto
authors: Kristin
authors: K
authors: Janz
authors: Michael
authors: M
authors: Lowe
authors: Patricia W
authors: PW
authors: Bedard
authors: Steve
authors: S
authors: Tam
authors: Li
authors: L
authors: Di
authors: Valerie
authors: V
authors: Clerin
authors: Natalia
authors: N
authors: Sushkova
authors: Boris
authors: B
authors: Tchernychev
authors: Desiree H H
authors: DH
authors: Tsao
authors: James C
authors: JC
authors: Keith
authors: Gray D
authors: GD
authors: Shaw
authors: Robert G
authors: RG
authors: Schaub
authors: Qin
authors: Q
authors: Wang
authors: Neelu
authors: N
authors: Kaila
mesh_terms: 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*
chemical_list: D006912:Hydroxyquinolines; D019007:P-Selectin; C528222:PSI-421; D012459:Salicylates