Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 24, Pages 9663-9679Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01367
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- U.S. Department of Energy [DE-AC02-05CH11231]
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The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 mu M) was optimized to lead compound 32 (AMG-0696; hcK hGKRP IC50 = 0.0038 mu M). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n(N) -> sigma*(S-X)) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GI( 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 32 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.
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