The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor

ACS Med Chem Lett. 2010 Apr 13;1(4):170-4. doi: 10.1021/ml100029k. eCollection 2010 Jul 8.


The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

Keywords: Human 5-lipoxygenase; MK-0633; leukotriene biosynthesis; respiratory diseases; setileuton.