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.
Subject(s)
Janus Kinase Inhibitors , Humans , Janus Kinase 1 , Janus Kinase 2 , Janus Kinase 3 , Janus Kinase Inhibitors/pharmacology , Janus Kinases , Phosphorylation , Protein Kinase Inhibitors/pharmacology , SolubilityABSTRACT
Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycogen Phosphorylase/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/pharmacology , Animals , Blood Glucose/analysis , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Disease Models, Animal , Hypoglycemic Agents/blood , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Molecular Conformation , Molecular Structure , Structure-Activity Relationship , Urea/pharmacology , ortho-Aminobenzoates/blood , ortho-Aminobenzoates/chemistryABSTRACT
Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.
Subject(s)
Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Diabetes Mellitus, Type 2/drug therapy , Glycogen Phosphorylase/antagonists & inhibitors , Imides/pharmacology , ortho-Aminobenzoates/pharmacology , Animals , Aryl Hydrocarbon Hydroxylases/chemistry , Crystallography, X-Ray , Cytochrome P-450 CYP2C9 , Dogs , Drug Design , Glycine/chemistry , Glycogen Phosphorylase/metabolism , Humans , Imides/chemistry , Inhibitory Concentration 50 , Liver/enzymology , Molecular Conformation , Rats , ortho-Aminobenzoates/chemistryABSTRACT
Optimization of the amino acid residue of a series of anthranilimide-based glycogen phosphorylase inhibitors is described leading to the identification of serine and threonine ether analogs. t-Butylthreonine analog 20 displayed potent in vitro inhibition of GPa, low potential for P450 inhibition, and excellent pharmacokinetic properties.
Subject(s)
Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Diabetes Mellitus, Type 2/drug therapy , Glycogen Phosphorylase/antagonists & inhibitors , Imides/chemistry , Serine/chemistry , Threonine/chemistry , ortho-Aminobenzoates/chemistry , Animals , Aryl Hydrocarbon Hydroxylases/chemistry , Crystallography, X-Ray , Cytochrome P-450 CYP2C9 , Drug Design , Glycine/chemistry , Glycogen Phosphorylase/metabolism , Humans , Inhibitory Concentration 50 , Liver/enzymology , Models, Chemical , RatsABSTRACT
A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure-activity relationships, and the discovery of a potent exemplar (IC(50)=80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.
