ABSTRACT
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase ß-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
Subject(s)
Benzeneacetamides/chemical synthesis , Diabetes Mellitus, Type 2/drug therapy , Enzyme Activators/chemical synthesis , Glucokinase/metabolism , Hypoglycemic Agents/chemical synthesis , Animals , Benzeneacetamides/pharmacokinetics , Benzeneacetamides/pharmacology , Dogs , Enzyme Activators/pharmacokinetics , Enzyme Activators/pharmacology , Female , Glucose/metabolism , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Lipidoses/metabolism , Liver/metabolism , Macaca fascicularis , Male , Mice , Mice, Inbred C57BL , Postprandial Period , Rabbits , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The 1 alpha-hydroxy A-ring phosphine oxide 1, a useful building block for vitamin D analogues, was synthesized from (S)-carvone in nine synthetic operations and a single chromatographic purification in 25% overall yield. The synthesis features two novel efficient synthetic transformations: the Criegee rearrangement of alpha-methoxy hydroperoxyacetate 10 in methanol to obtain directly the desired secondary 3 beta-alcohol 11 and the highly chemo- and stereoselective isomerization of dieneoxide ester (E)-7 to the 1 alpha-allylic alcohol with an exocyclic double bond (E)-8. Further insight into the selectivity control of the latter rearrangement was obtained from the reactions of (Z)-epimeric substrates. The new synthetic approach leading to the 1 alpha-hydroxy epimers complements our previously reported synthesis of the corresponding 1 beta-epimers, thus producing all stereoisomers of these versatile building blocks efficiently from carvone.
