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
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
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DOI：
10.1021/jm9013696
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发表时间：
2010-08-26
影响因子：
7.3
通讯作者：
Kaila, Neelu
中科院分区：
文献类型：
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作者：
Huang, Adrian;Moretto, Alessandro;Kaila, Neelu
先前，我们报道了PSI-697（1a）的发现，PSI-697（1a）是一种基于C-2苄基取代的喹啉水杨酸的P-选择素抑制剂。它在多种心血管疾病动物模型中具有活性。在1期单次递增剂量研究中，化合物1a在高达1200 mg的剂量下在健康志愿者中也显示出良好的耐受性和安全性。然而，其口服生物利用度较低。我们的目标是确定一种具有同等效力、增加溶解度和增加暴露量的备用化合物。我们通过在C-2苄基侧链的α位上支化和通过喹啉的羧基A环上的取代基的修饰来扩展我们在这一系列中的结构活性研究。这导致PSI-421的发现，其水溶性和药代动力学性质显著改善。该化合物已在动脉和静脉损伤的动物模型中显示出口服疗效，并被选为临床前开发化合物，用于治疗动脉粥样硬化和深静脉血栓形成等疾病。
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.