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 α 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.

中文翻译：

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在模型中发现具有改善的药代动力学特性和口服功效的P-选择素抑制剂2- [1-（4-氯苯基）环丙基] -3-羟基-8-（三氟甲基）喹啉-4-羧酸（PSI-421）血管损伤

以前，我们报道了基于C-2苄基取代喹啉水杨酸的P-选择素抑制剂PSI-697（1a）的发现。它在多种心血管疾病的动物模型中都很活跃。化合物1a在第1期单次上升剂量研究中，在高达1200 mg的健康志愿者中也显示出良好的耐受性和安全性。但是，其口服生物利用度低。我们的目标是确定具有相同效力，增加的溶解度和增加的暴露量的备用化合物。我们通过在C-2苄基侧链的α位置分支和通过修饰喹啉的羧基A环上的取代基扩展了我们在该系列中的结构活性研究。这导致发现了PSI-421，其水溶性和药代动力学特性得到了显着改善。该化合物已在动脉和静脉损伤的动物模型中显示出口服功效，并被选作临床前开发化合物，可用于治疗诸如动脉粥样硬化和深静脉血栓形成的疾病。