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(+)-Geodin (1) was isolated from Penicillium glabrum AJ117540 with activity that stimulates glucose uptake by rat adipocytes. Unlike insulin it is active in the presence of wortmannin. Dihydrogeodin (2) and sulochrin (3) which are the precursors of (+)-geodin biosynthesis were also isolated from the same fungus. Preliminary SAR studies of 1 showed some analogues had enhanced activity. Especially, the activities of racemic geodin and dibromo analogue (7a) were comparable to that of the natural product. Geodin (1), a known fungal metabolite, was isolated from Penicillium glabrum AJ117540 as an active substance (Fig. 1). Dihydrogeodin (2) and sulochrin (3), the precursors of 1, were also isolated from the same fungal extract. In this study, preliminary mechanistic insight and SAR are reported.

An early defect in Type 2 diabetes is the loss of acute insulin release after food intake, which causes prolonged elevation of postprandial glucose levels. Suppressing postprandial hyperglycemia is considered to be very important for preventing diabetic complications. Sulfonylureas are well-known insulin secretagogues and have been widely used in the treatment of Type 2 diabetes. These agents, however, do not appear to be able to ameliorate impairment of the first phase of insulin secretion and postprandial hyperglycemia. Nateglinide, which is a derivative of D-phenylalanine, is a non-sulfonylurea insulin secretagogue. Although the in vitro insulin-releasing effect of nateglinide is similar to that of sulfonylureas, its hypoglycemic effect is more rapid and short lasting. The in vivo unique pharmacodynamic profile of nateglinide is likely to result from its rapid absorption and elimination. This novel antidiabetic agent has made it possible to compensate for the impaired first phase insulin response and thus suppresses postprandial hyperglycemia. In clinical trials, nateglinide reduced prandial glucose excursion and improved early phase of insulin release dose-dependently after 12 weeks treatment. Nateglinide is a highly physiologic mealtime glucose regulator, which rapidly increases insulin secretion when taken before meals, mimicking early-phase insulin release lost in patients with Type 2 diabetes.

Outer mitochondrial membrane cytochromeb 5 (OMb), which is an isoform of cytochromeb 5 (cyt b 5) in the endoplasmic reticulum, is a typical tail-anchored protein of the outer mitochondrial membrane. We cloned cDNA containing the complete amino acid sequence of OMb and found that the protein has no typical structural feature common to the mitochondrial targeting signal at the amino terminus. To identify the region responsible for the mitochondrial targeting of OMb, various mutated proteins were expressed in cultured mammalian cells, and the subcellular localization of the expressed proteins was analyzed. The deletion of more than 11 amino acid residues from the carboxyl-terminal end of OMb abolished the targeting of the protein to the mitochondria. When the carboxyl-terminal 10 amino acids of OMb were fused to the cytb 5 that was previously deleted in the corresponding 10 residues, the fused protein localized in the mitochondria, thereby indicating that the carboxyl-terminal 10 amino acid residues of OMb have sufficient information to transport OMb to the mitochondria. The replacement of either of the two positively charged residues within the carboxyl-terminal 10 amino acids by alanine resulted in the transport of the mutant proteins to the endoplasmic reticulum. The mutant cyt b 5, in which the acidic amino acid in its carboxyl-terminal end was replaced by basic amino acid, could be transported to the mitochondria. It would thus seem that charged amino acids in the carboxyl-terminal portion of these proteins determine their locations in the cell.

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) is a nonsulfonylurea hypoglycemic agent that decreases blood glucose levels in nondiabetic and diabetic animals. In the present study, we attempted to determine the effect of A-4166 on hormone secretion from the in vitro-perfused rat pancreas and to examine the underlying secretory mechanisms. In the presence of basal glucose (3 mmol/L), A-4166 markedly stimulated insulin and somatostatin release in a concentration-dependent manner over 0.03 to 3 mmol/L. A sulfonylurea, tolbutamide, also stimulated insulin and somatostatin release. A-4166 and tolbutamide elevated the level of glucagon release; however, the change lacked a clear concentration-dependent property. A-4166 at 0.3 mmol/L and tolbutamide at 3 mmol/L exhibited maximal stimulation of insulin release to a similar extent, indicating that A-4166 is one log-order more potent than and as effective as tolbutamide. By contrast, A-4166 stimulated somatostatin release to a threefold greater extent than tolbutamide. A-4166 evoked an increase in the cytosolic free-Ca2+ concentration ([Ca2+]i) in rat pancreatic beta cells. [Ca2+]i and insulin secretory responses to A-4166 were inhibited by nitrendipine (NTD), a blocker of the L-type Ca2+ channel, and by diazoxide (DAZ), an opener of the adenosine triphosphate (ATP)-sensitive K+ channel. Furthermore, A-4166-stimulated somatostatin release was also inhibited by NTD and by DAZ. The results indicate that A-4166 and tolbutamide stimulate the release of insulin and somatostatin, and that A-4166 is much more effective than tolbutamide in releasing somatostatin, a hormone that attenuates hyperglycemia under certain circumstances. It is concluded that A-4166-induced insulin release is mediated by an increase in [Ca2+]i in beta cells. An inhibition of ATP-sensitive K+ channels and a consequent activation of L-type Ca2+ channels appear to play a key role not only in insulin secretion from beta cells, but also in somatostatin secretion from delta cells in response to A-4166.

(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) is a new nonsulfonylurea hypoglycemic agent that lowers blood glucose by stimulating insulin release. In the present study, we examined the effects of A-4166, voglibose (an alpha-glucosidase inhibitor), and glibenclamide (a sulfonylurea) on the postprandial glycemic increase in rats with or without diabetes mellitus. Oral administration of A-4166 (25-100 mg/kg) dose-dependently decreased blood glucose with a rapid onset and short duration in normal rats. On the other hand, glibenclamide (1-4 mg/kg) showed a slower onset of its hypoglycemic action, and voglibose (0.2 mg/kg) had no effect. In the case of postprandial glucose excursion, the carbohydrate-induced increase in blood glucose was reduced by oral administration of either A-4166 or voglibose without causing sustained hypoglycemia in both normal and neonatal streptozotocin-induced diabetic rats. However, the efficacy of voglibose varied with the type of carbohydrate load. Glibenclamide produced a prolonged decrease in blood glucose without any appreciable effect on the initial glucose excursion. After sucrose loading, plasma insulin levels during the initial 1 h were significantly higher in A-4166-treated rats than in control rats, while voglibose completely inhibited the insulin response to sucrose. In glibenclamide-treated rats, an augmented insulin response was not seen. In conclusion, unlike other hypoglycemic agents, A-4166 suppresses postprandial glucose excursions by stimulating the early phase of insulin secretion.