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
| Autor: | Steve Tam, Qin Wang, Adrian Huang, Desiree H.H. Tsao, Natalia Sushkova, Michael Dennis Lowe, Gray D. Shaw, Patricia W. Bedard, Li Di, Boris Tchernychev, James C. Keith, Neelu Kaila, Robert G. Schaub, Kristin Janz, Valerie Clerin, Alessandro Moretto |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Cell Membrane Permeability Carboxylic acid Administration Oral Pharmacology Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Stability Pharmacokinetics Drug Discovery Animals Humans Potency Structure–activity relationship Leukocyte Rolling Venous Thrombosis chemistry.chemical_classification Trifluoromethyl Quinoline Salicylates Rats Bioavailability Mice Inbred C57BL Macaca fascicularis P-Selectin Solubility chemistry Hydroxyquinolines Microsomes Liver Molecular Medicine Caco-2 Cells Carotid Artery Injuries Salicylic acid Papio |
| Zdroj: | Journal of Medicinal Chemistry. 53:6003-6017 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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