Selective inhibitors of 12(s)-lipoxygenase (12-lox) and methods for use of same

Abstract

Disclosed herein are small molecule inhibitors of 12(S)-Lipoxygenase (12-LOX), and methods of using the small molecules to inhibit 12-LOX activation and to treat diseases, such as platelet hemostasisand thrombosis. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 658,936, filed April 17, 2018, the entire disclosure of which is hereby incorporated by reference. technical field [0003] The present disclosure relates to small molecule inhibitors of 12(S)-lipoxygenase ("12-LOX"), and methods of using the small molecules to inhibit 12-LOX activation and treat diseases such as platelet hemostasis and thrombosis. Background technique [0004] Platelet adhesion and aggregation at sites of vascular injury are essential to maintain normal hemostasis and prevent blood loss. However, when atherosclerotic plaque rupture compromises the integrity of the vessel wall, the same process can also lead to arterial thrombosis and the formation of vessel occlusions. See Ruggeri ZM, Nat Med., 8:1227-1234 (2002). Excessive platelet activation and aggregation can lead to occlusive thrombosis with serious consequences suc...

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However, the limited solubility of ML355 greatly reduces its clinical use

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