Thoma, Gebhard, Decoret, Odile, Vangrevelinghe, Eric, Trunzer, Markus, Decker, Andrea, Bruno, Sandro, Hauchard, Alice and Hacini-Rachinel, Feriel (2023) Design of a Super-Soft Topical JAK Inhibitor, which Is Efficacious in Human Skin but Rapidly Deactivated in Blood. Journal of medicinal chemistry, 66. pp. 15042-15053.

Abstract

We describe the discovery and characterization of the super-soft topical JAK inhibitor 3(R), which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester 3(R) is rapidly hydrolyzed (t1/2~6 min) to the corresponding charged carboxylic acid 4 exhibiting >30-fold reduced permeability. Consequently, acid 4 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 the topically active ester 3(R) at a rate beyond the maximal hepatic clearance.

Item Type:	Article
Keywords:	JAK kinases, soft drug, topical, inhibitor
Date Deposited:	07 Dec 2023 00:45
Last Modified:	07 Dec 2023 00:45
URI:	https://oak.novartis.com/id/eprint/51818