Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n_N → σ*_S–X) Interaction for Conformational Constraint

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK–GKRP disrupters are revealed. Diarylmethane­sulfonamide hit <b>6</b> (hGK–hGKRP IC₅₀ = 1.2 μM) was optimized to lead compound <b>32</b> (AMG-0696; hGK–hGKRP IC₅₀ = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n_N → σ*_S–X) in <b>32</b> was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound <b>32</b> was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = −45%; 100 mg/kg po, 3 h). X-ray analyses of <b>32</b> and several precursors bound to GKRP were also obtained. This novel disrupter of GK–GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design

Discovery and in Vivo Evaluation of (<i>S</i>)‑<i>N</i>‑(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)‑9<i>H</i>‑purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of <b>1</b> (AMG319), a compound with an IC₅₀ of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation