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Kaila, N. et al.

Kaila, Janz, Huang, Moretto, Debernardo, Bedard, Tam, Clerin, Keith, Tsao, Sushkova, Shaw, Camphausen, Schaub, Wang,

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.[1]

References

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. Kaila, N., Janz, K., Huang, A., Moretto, A., Debernardo, S., Bedard, P.W., Tam, S., Clerin, V., Keith, J.C., Tsao, D.H., Sushkova, N., Shaw, G.D., Camphausen, R.T., Schaub, R.G., Wang, Q. J. Med. Chem. (2007) [Pubmed]

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