Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists.
Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.
Kaila
Neelu
N
Chemical and Screening Sciences, Cardiovascular and Metabolic Disease, Drug Safety and Metabolism, Inflammation, Wyeth Research, Cambridge, Massachusetts 02140, USA. nkaila@wyeth.com
Janz
Kristin
K
DeBernardo
Silvano
S
Bedard
Patricia W
PW
Camphausen
Raymond T
RT
Tam
Steve
S
Tsao
Desirée H H
DH
Keith
James C
JC
Nickerson-Nutter
Cheryl
C
Shilling
Adam
A
Young-Sciame
Ruth
R
Wang
Qin
Q
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D016208:Databases, Factual; D004487:Edema / Q000188:drug therapy; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; 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
C517636:2-(4-chlorophenyl)-3-hydroxy-8-phenylquinoline-4-carboxylic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065607:Cytochrome P-450 Enzyme Inhibitors; D006912:Hydroxyquinolines; D019007:P-Selectin; D011804:Quinolines; D012459:Salicylates