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

  • J Med Chem. 2023 Nov 9;66(21):15042-15053. doi: 10.1021/acs.jmedchem.3c01735.
Gebhard Thoma  1 ,  Odile Decoret  1 ,  Eric Vangrevelinghe  1 ,  Markus Trunzer  2 ,  Andrea Decker  3 ,  Anette Orjuela Leon  4 ,  Christian Beerli  4 ,  Sandro Bruno  4 ,  Alice Hauchard  4 ,  Guido Paulat  4 ,  Hans-Guenter Zerwes  4 ,  Feriel Hacini-Rachinel  4
Affiliations
  • 1. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • 2. PK Sciences, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
  • 3. Chemical and Pharmaceutical Profiling, Global Drug Development, Novartis Pharma AG, 4002 Basel, Switzerland.
  • 4. Immunology Disease Area, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
PMID: 37906573 DOI: 10.1021/acs.jmedchem.3c01735
Abstract

We describe the discovery and characterization of the supersoft 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 topically active ester 3(R) at a rate beyond the maximal hepatic clearance.

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