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The inappropriate overproduction of glucose by the liver is one of the key contributors to the hyperglycaemia of the diabetic state, and thus is a logical site of intervention for novel anti-diabetic approaches. Metformin is the only currently marketed anti-hyperglycaemic drug whose action is attributed largely to its having inhibitory effects on hepatic glucose production, but its molecular site and mechanism(s) of action remain unknown, whereas the liver acting PPAR alpha agonists have their effects primarily on lipid metabolism. This review therefore rather focuses on candidate molecular targets within the liver for anti-hyperglycaemic therapy, and describes potential rate-controlling receptors and enzymes within the glucose producing pathways (glycogenolysis and gluconeogenesis). Most focus is directed towards inhibitors of the enzymes glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase, and towards glucagon receptor antagonists, as these appear to be the most advanced in preclinical and clinical development, although progress with other potential targets is also described. Evidence of the anti-diabetic potential of such agents from animal studies is presented, and the relative merits of each approach are reviewed and compared. It is likely that such agents will become important additions to the therapeutic approaches to combat diabetes.

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Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors. Their synthesis, mode of binding to the allosteric AMP site as well as in vitro data on GP inhibition are shown. The most potent inhibitor was found to be 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (4j) with an IC(50) value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.

Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC(50) = 0.4-1.2 microM) and of basal and glucagon-stimulated glycogenolysis (IC(50) = 1-3 microM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.

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1 U-84935, diimidazo[1,5-a; 1',2'-C]quinazoline,5-(5-cyclopropyl-l,2,4-oxidiazol-3yl)-2,3-dihydro, is a ligand of high affinity for the benzodiazepine site of the GABAA receptor composed of a1P2Y2 subunits.2 The efficacy of its analogues was measured with their ability to potentiate GABA-mediated C1-currents in the whole cell configuration of the patch clamp techniques in human kidney cells (A293 cells) expressing the subtype of the GABAA receptor. 3 The analogues displayed various levels of efficacy including agonists, partial agonists and antagonists without marked changes in their affinity for the receptors. 4 The major determinant of their efficacy was the spacial configuration of a methyl substituent of the C2 atom of the rigid and planar diimidazoquinazoline ring: U-90167, containing the methyl substituent projected below the plane of the ring, markedly enhanced the GABA current with a maximal potentiation of 220 ± 25%, while its stereoisomer, U-90168, marginally increased the GABA response with a maximal potentiation of 45 ± 10%, to which its methyl group appeared to contribute very little. S U-90167 potentiated the GABA response with an EC50 of 8.1 nM and a Hill coefficient of 1.1 and did not alter the reversal potential for the Cl-current. 6 From computational modelling, the sensitive methyl group of U-90167 could be assigned to the general region for the 5-phenyl group of diazepam. The diimidazoquinazoline, because of its rigid and plantar ring structure, may be useful to define further the out-of-plane region responsible for agonistic activity and to pinpoint other areas pivotal to the functionality of benzodiazepine ligands.

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