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

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.