Design of a Supersoft Topical JAK Inhibitor, Which Is Effective in Human Skin but Rapidly Deactivated in Blood.

We describe the discovery and characterization of the supersoft topical JAK inhibitor , which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester is rapidly hydrolyzed ( ∼ 6 min) to the corresponding charged carboxylic acid exhibiting >30-fold reduced permeability. Consequently, acid does not reach the intracellular JAK kinases and is inactive in cellular assays and in blood. Thus, hydrolysis by blood esterases leads to the rapid deactivation of topically active ester at a rate beyond the maximal hepatic clearance.