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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 µM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 µM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → s*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 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 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. [ABSTRACT FROM AUTHOR]

Theglucokinase–glucokinase regulatory protein (GK-GKRP)complex plays an important role in controlling glucose homeostasisin the liver. We have recently disclosed a series of arylpiperazinesas in vitro and in vivo disruptors of the GK-GKRP complex with efficacyin rodent models of type 2 diabetes mellitus (T2DM). Herein, we describea new class of aryl sulfones as disruptors of the GK-GKRP complex,where the central piperazine scaffold has been replaced by an aromaticgroup. Conformational analysis and exploration of the structure–activityrelationships of this new class of compounds led to the identificationof potent GK-GKRP disruptors. Further optimization of this novel seriesdelivered thiazole sulfone 93, which was able to disruptthe GK-GKRP interaction in vitro and in vivo and, by doing so, increasescytoplasmic levels of unbound GK. [ABSTRACT FROM AUTHOR]

Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzodthiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist rTRPV1(CAP) IC503.7 nM with excellent aqueous solubility (≥200 g/mL in 0.01 N HCl) and a reduced half-life (rat t123.8 h, dog t122.7 h, monkey t123.2 h) as compared to AMG 517. In addition, compound 16pwas shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED501.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED 1 mg/kg, p.o). Based on its improved overall profile, compound 16p(AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain. [ABSTRACT FROM AUTHOR]

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cisconformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC504.5 and 0.6 nM, respectively) and human TRPV1 (IC507.4 and 3.7 nM, respectively). In addition, compound 74was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats. [ABSTRACT FROM AUTHOR]