title: 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]quinoline-4-carboxylic acid (PSI-697): identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists.
abstract: P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
authors.affiliation: Chemical and Screening Sciences, Cardiovascular and Metabolic Disease, Drug Safety and Metabolism, Wyeth Research, Cambridge, Massachusetts 02140, USA. nkaila@wyeth.com
authors.forename: Neelu
authors.initials: N
authors.lastname: Kaila
authors.forename: Kristin
authors.initials: K
authors.lastname: Janz
authors.forename: Adrian
authors.initials: A
authors.lastname: Huang
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretto
authors.forename: Silvano
authors.initials: S
authors.lastname: DeBernardo
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Bedard
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Valerie
authors.initials: V
authors.lastname: Clerin
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Desirée H H
authors.initials: DH
authors.lastname: Tsao
authors.forename: Natalia
authors.initials: N
authors.lastname: Sushkova
authors.forename: Gray D
authors.initials: GD
authors.lastname: Shaw
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Camphausen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000517:prevention & control*; D016893:Carotid Stenosis / Q000517:prevention & control; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001057:Apolipoproteins E; D005343:Fibrinolytic Agents; D006912:Hydroxyquinolines; D007211:Indoles; D019007:P-Selectin; D011804:Quinolines; D012459:Salicylates; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid