Eyes on Topical Ocular Disposition: The Considered Design of a Lead Janus Kinase (JAK) Inhibitor That Utilizes a Unique Azetidin-3-Amino Bridging Scaffold to Attenuate Off-Target Kinase Activity, While Driving Potency and Aqueous Solubility

  • J Med Chem. 2023 Jul 13;66(13):8929-8950. doi: 10.1021/acs.jmedchem.3c00519.
Heeren M Gordhan  1 ,  Steven T Miller  1 ,  Daphne C Clancy  1 ,  Maria Ina  1 ,  Alan V McDougal  1 ,  D'Quan K Cutno  1 ,  Robert V Brown  1 ,  Cynthia L Lichorowic  2 ,  Jill M Sturdivant  1 ,  Kyle A Vick  3 ,  Stuart S Williams  1 ,  Mitchell A deLong  1 ,  Jeffrey C White  4 ,  Casey C Kopczynski  1 ,  David A Ellis  1
Affiliations
  • 1. Alcon Research, LLC, Durham, North Carolina 27703, United States.
  • 2. Sage Therapeutics, Inc., Boston, Massachusetts 02142, United States.
  • 3. ID Business Solutions, Ltd., Boston, Massachusetts 02210, United States.
  • 4. Baxter Healthcare Corp., Deerfield, Illinois 60015, United States.
PMID: 37314941 DOI: 10.1021/acs.jmedchem.3c00519
Abstract

An unmet medical need remains for patients suffering from dry eye disease (DED). A fast-acting, better-tolerated noncorticosteroid anti-inflammatory eye drop could improve patient outcomes and quality of life. Herein, we describe a small-molecule drug discovery effort to identify novel, potent, and water-soluble JAK inhibitors as immunomodulating agents for topical ocular disposition. A focused library of known 3-(4-(2-(arylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitriles was evaluated as a molecular starting point. Structure-activity relationships (SARs) revealed a ligand-efficient (LE) JAK Inhibitor series, amenable to aqueous solubility. Subsequent in vitro analysis indicated the potential for off-target toxicity. A KINOMEscan selectivity profile of 5 substantiated the likelihood of widespread series affinity across the human kinome. An sp2-to-sp3 drug design strategy was undertaken to attenuate off-target kinase activity while driving JAK-STAT potency and aqueous solubility. Tactics to reduce aromatic character, increase fraction sp3 (Fsp3), and bolster molecular complexity led to the azetidin-3-amino bridging scaffold in 31.

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