Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic Acid (PSI-421), a P-Selectin Inhibitor with Improved Pharmacokinetic Properties and Oral Efficacy in Models of Vascular Injury

1区 · 医学

Article

作者: Wang, Qin ; Tam, Steve ; Shaw, Gray D. ; Tsao, Desiree H. H. ; Schaub, Robert G. ; Sushkova, Natalia ; Clerin, Valerie ; Lowe, Michael ; Di, Li ; Huang, Adrian ; Janz, Kristin ; Kaila, Neelu ; Keith, James C. ; Tchernychev, Boris ; Moretto, Alessandro ; Bedard, Patricia W.

Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.

2008-01-01·Thrombosis and haemostasis2区 · 医学

Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation

2区 · 医学

Article

作者: Frank J. Londy ; Nicole E. Ballard ; Neelu Kaila ; Shirley K. Wrobleski ; Thomas R. Meier ; Daniel D. Myers ; Paul J. Zajkowski ; Angela E. Hawley ; George P. Vlasuk ; Patricia W. Bedard ; Thomas W. Wakefield ; Robert G. Schaub

Summary:

P-selectin inhibition has been evaluated as a therapeutic for prevention and treatment of venous thrombosis. In this study, a novel oral small-molecule inhibitor of P-selectin, PSI-421, was evaluated in a baboon model of stasis induced deep vein thrombosis (DVT). Experimental groups included i) primates receiving a single oral dose of 1 mg/kg PSI-421 two days prior and continued six days after thrombosis (n=3); ii) primates receiving a single daily subcutaneous dose of 0.57 mg/kg enoxaparin sodium two days prior and continued six days post thrombosis (n=3); and iii) primates receiving no treatment (n=3).PSI-421 treated primates had greater percent vein reopening and less vein wall inflammation than the enoxaparin and controls at day 6. Microparticle tissue factor activity (MPTFA) was significantly lower in the animals receiving PSI-421 immediately after thrombosis (T+6 hours day 0) suggesting lower potential for thrombogenesis in these animals. PSI-421 also reduced soluble P-selectin levels versus controls at T+6 hours day 0, day 2 and 6. Experimental animals in any group showed no adverse effects on coagulation. This study is the first to demonstrate a reduction in MPTFA associated with vein reopening and reduced vein inflammation due to oral P-selectin inhibition in a baboon model of DVT.

100 项与 PSI-421 相关的药物交易

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