Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.

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 β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

Reaction of trimethyl‐hydroquinone with methyl vinyl ketone in acidic methanol gave rac.‐2‐methoxy‐2,5,7,8‐tetramethyl‐chroman‐6‐ol (8). This acetal was converted in four steps to rac.‐(6‐hydroxy‐2,5,7,8‐tetramethyl‐chroman‐2‐yl)acetic acid (13). Acid 13 was readily resolved with α‐methyl‐benzylamine to give the (S)‐enantiomer 14. Treatment of the unwanted (2 R)‐isomer with acid regenerated 13, thus leading to an efficient use of this compound. Employing a side chain derived from phytol, 14 was converted to (2R, 4′R, 8′R)‐α‐tocopherol (1d, ‘natural’ vitamin E). A reaction sequence from 14 involving two highly stereoselective Claisen rearrangements has provided the first total synthesis of (2R,'E,7′E)‐α‐tocotrienol (2d).

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

Sixty-two congeners of vinblastine (VLB), primarily with modifications of the piperidine ring in the carbomethoxycleavamine moiety of the binary alkaloid, were synthesized and evaluated for cytotoxicity against murine L1210 leukemia and RCC-2 rat colon cancer cells, and for their ability to inhibit polymerization of microtubular protein at < 10(-6) M, and for induction of spiralization of microtubular protein, and for microtubular disassembly at 10(-4) M concentrations. An ID50 range of >10(7) M concentrations was found for L1210 inhibition by these compounds, with the most active 1000x as potent as vinblastine.

9-Chloro-7-(2-chlorophenyl)pyrimido [5,4-d][2]benzazepine, a potent anxiolytic agent, was synthesized in three steps from 4-chloro-5-methylpyrimidine and 2-iodo-2',5-dichlorobenzophenone In the key step these materials were coupled in an unsymmetrical biaryl synthesis mediated with zerovalent nickel. The methyl group of the resulting product was brominated with NBS, and the seven-membered ring was closed with ammonia. Three byproducts of the coupling reaction were isolated and characterized. They proved to be 5,5'-dimethyl-4,4'-bipyrimidinyl, 4,4'-dichloro-2,2'-bis(o-chlorobenzoyl)biphenyl, and 2-chloro-9-fluorenone. An improved procedure for the Sandmeyer conversion of aminobenzophenones to iodobenzophenones is also described. Under conditions for palladium-catalyzed coupling of the ketone with terminal acetylenes, the oximes of 2-iodo-2',5-dichlorobenzophenone undergo cyclization to a 1,2-benzisoxazole or reductive loss of iodine, depending on whether the Z or E oxime is used.

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