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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we describea new class of aryl sulfones as disruptors of the GK-GKRP complex,where the central piperazine scaffold has been replaced by an aromaticgroup.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]

A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure−activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11β-HSD1 Ki= 35 nM and negligible PXR activity. Compound (S)-33awas advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11β-HSD1 activity after being orally administered. [ABSTRACT FROM AUTHOR]

11-hydroxysteroid dehydrogenase type 1 (11-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Kiof 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model. [ABSTRACT FROM AUTHOR]