Transition Metal Complexes with Appended Benzimidazole Groups for Sensing Dihydrogenphosphate.

Four new complexes [Ru(bpy)2(bbib)](PF6)2, [Ru(phen)2(bbib)](PF6)2, [Re(CO)3(bbib)(py)](PF6) and [Ir(ppy)2(bbib)](PF6) [where bbib = 4,4'-bis(benzimidazol-2-yl)-2,2'-bipyridine] have been prepared and their photophysical properties determined. Their behaviour has been studied with a variety of anions in acetonitrile, DMSO and 10% aquated DMSO. Acetate and dihydrogenphosphate demonstrate a redshift in the bbib ligand associated absorptions suggesting that the ligand is strongly interacting with these anions. The 3MLCT emissive state is sensitive to the introduction of small quantities of anion (sub-stoichiometric quantities) and significant quenching is typically observed with acetate, although this is less pronounced in the presence of water. The emissive behaviour with dihydrogenphosphate is variable, showing systematic changes as anion concentration increases with several distinct interactions evident . 1H NMR and 31P NMR titrations in a 10% D2O - D6-DMSO mixture suggest that with dihydrogenphosphate, the imidazole group able to act as both a proton acceptor and donor. It appears that all four complexes can form a {[complex]2-H2PO4} "dimer", a one-to-one species (which the X-ray crystallography study suggests is dimeric in the solid-state), and a complex with a combined bis(dihydrogenphosphate) complex anion. The speciation relies on complex equilibria dependent on several factors including the complex charge, the hydrophobicity of the associated ligands, and the solvent.

Optimisation of pharmacokinetic properties in a neutral series of 11ß-HSD1 inhibitors.

11ß-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11ß-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.

Novel acidic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).

Inhibition of 11ß-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.