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.
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.
Kaila
Neelu
N
Chemical and Screening Sciences, Cardiovascular and Metabolic Disease, Drug Safety and Metabolism, Wyeth Research, Cambridge, Massachusetts 02140, USA. nkaila@wyeth.com
Janz
Kristin
K
Huang
Adrian
A
Moretto
Alessandro
A
DeBernardo
Silvano
S
Bedard
Patricia W
PW
Tam
Steve
S
Clerin
Valerie
V
Keith
James C
JC
Tsao
Desirée H H
DH
Sushkova
Natalia
N
Shaw
Gray D
GD
Camphausen
Raymond T
RT
Schaub
Robert G
RG
Wang
Qin
Q
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
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