文摘
The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK–GKRP disrupters are revealed. Diarylmethanesulfonamide hit <b>6b> (hGK–hGKRP ICb>50b> = 1.2 μM) was optimized to lead compound <b>32b> (AMG-0696; hGK–hGKRP ICb>50b> = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nb>Nb> → σ*b>S–Xb>) in <b>32b> was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound <b>32b> 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>32b> 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.