Fig. 11.

Key stages in the hit to lead pathway of UCT943. Initial change the phenyl substituents with a single trifluoromethyl group led to greater in vivo stability. Introduction of piperazine amide instead of methylsulfonyl and a pyrazine instead of a pyridine led to the improved solubility and potency of the optimized compound. Surprisingly, introduction of a nitrogen in the red circle resulted in complete inactivity in vivo