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Publication Abstract from PubMed

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 sp(2)-to-sp(3) 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 sp(3) (Fsp(3)), and bolster molecular complexity led to the azetidin-3-amino bridging scaffold in 31.

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.,Gordhan HM, Miller ST, Clancy DC, Ina M, McDougal AV, Cutno DK, Brown RV, Lichorowic CL, Sturdivant JM, Vick KA, Williams SS, deLong MA, White JC, Kopczynski CC, Ellis DA J Med Chem. 2023 Jul 13;66(13):8929-8950. doi: 10.1021/acs.jmedchem.3c00519. Epub , 2023 Jun 14. PMID:37314941^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.