Fig. 21

Key stages in the hit to lead pathway of (+)-SJ733. Poor metabolic stability of the hit compound was addressed by replacement of the chloro and methoxy groups with cyano and fluoro groups respectively. Further in vivo stability and solubility improvements were made by changing the thiophene to a pyridine. Finally, the gem-dimethyl group was substituted with a trifluoromethyl group to eliminate possible metabolic oxidation