Document Report Card

ID: ALA1139219

Journal: J Med Chem

Title: Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists.

Authors: Kaila N, Janz K, DeBernardo S, Bedard PW, Camphausen RT, Tam S, Tsao DH, Keith JC, Nickerson-Nutter C, Shilling A, Young-Sciame R, Wang Q.

Abstract: 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.

CiteXplore: 17201408

DOI: 10.1021/jm0602256