Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, Rt. 206 and Province Line Road, Princeton, NJ 08543 (USA).
ChemMedChem. 2014 Oct;9(10):2327-43. doi: 10.1002/cmdc.201402141. Epub 2014 Jul 2.
Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.
目前的抗血栓形成药物研发工作的目标是开发出比现有治疗标准更有效减少血栓形成且出血风险更小的化合物。临床前数据表明，P2Y1 拮抗剂的出血风险可能低于 P2Y12 拮抗剂，同时提供类似的抗血栓形成效果。本文描述了我们在一系列 7-羟基吲哚啉二芳基脲中的连续 SAR 研究。当以口服剂量给药时，4-三氟甲基-7-羟基-3,3-二甲基吲哚啉类似物 4 在大鼠动脉血栓形成模型中具有高度疗效，出血有限。然后，通过一种新的一步合成将 4 中不稳定的 CF3 基团转化为各种基团，得到了一系列有效的 P2Y1 拮抗剂。其中，4-苯并噻唑取代的吲哚啉具有理想的大鼠 PK 特性，具体而言，清除率低，分布容积小。此外，化合物 40 具有较高的静脉内暴露量和适度的生物利用度，使其具有最佳的整体特征。
