David Haigh

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

BACKGROUND Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3. RESULTS SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase. CONCLUSIONS SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3).

Potent 3-anilino-4-arylmaleimide glycogen synthase kinase-3 (GSK-3) inhibitors have been prepared using automated array methodology. A number of these are highly selective, having little inhibitory potency against more than 20 other protein kinases.

The synthesis of BRL 49653 - a novel and potent antihyperglycaemic agent

Abstract Modifications based upon a metabolite of ciglitazone afforded BRL 49653, a novel potent insulin sensitizer. A facile synthesis of this compound is described.

5-Aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3)

Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.

Non thiazolidinedione antihyperglycaemic agents. 1: α-Heteroatom substituted β-phenylpropanoic acids

The 5-benzylthiazolidine-2,4-dione moiety of insulin sensitising antidiabetic agents can be replaced by a range of α-heteroatom functionalised β-phenylpropanoic acids. α-Oxy-carboxylic acids show potent antidiabetic activity and one compound, the α-ethoxyacid 15 (SB 213068), is one of the most potent antihyperglycaemic agents yet reported.

Asymmetric rhodium carbenoid insertion into the Si-H bond

Abstract Decomposition of methyl 2-diazophenylacetate in the presence of dimethylphenylsilane and a chiral dirhodium(II) catalyst results in SiH insertion of the intermediate carbenoid with varying degrees of enantioselectivity (up to 47% ee).

Non-thiazolidinedione antihyperglycaemic agents. Part 3 : The effects of stereochemistry on the potency of α-methoxy-β-phenylpropanoic acids

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARgamma (peroxisomal proliferator activated receptor gamma), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

New members of the chiral pool: β-Hydroxypiperidine carboxylates from Baker's yeast reductions of the corresponding keto-esters

Abstract Bakers yeast reduction of the keto-piperidinecarboxylates 2 and 6 leads to the corresponding hydroxy-esters 3 and 7a in good chemical yields and with >99% d.e. and > 93% e.e. in both cases.

The carbenoid approach to peptide synthesis

A different approach to the synthesis of dipeptides is described based on the formation of the NHCHR1CONH-CHR2CO bond by carbenoid N-H insertion, rather than the formation of the peptide bond itself. Thus decomposition of triethyl diazophosphonoacetate catalysed by rhodium(II) acetate in the presence of N-protected amino acid amides 8 gives the phosphonates 9. Subsequent Wadsworth-Emmons reaction of 9 with aldehydes in the presence of DBU gives dehydro dipeptides 10. The reaction has been extended to a simple two-step procedure, without the isolation of the intermediate phosphonate, for conversion of a range of amino acid amides 11 into dehydro dipeptides 12 and to an N-methylamide 11 h, and for conversion of a dipeptide to tripeptide (13-->14). Direct conversion, by using methyl diazophenylacetate, of amino acid amides to phenylglycine-containing dipeptides 19 proceeds in good chemical yield, but with poor diastereoselectivity.

Asymmetric rhodium carbene insertion into the SiH bond: identification of new dirhodium(II) carboxylate catalysts using parallel synthesis techniques

Abstract Decomposition of methyl 2-diazophenylacetate in the presence of silanes and a chiral dirhodium(II) catalyst results in SiH insertion of the intermediate carbenoid with varying degrees of enantioselectivity. New chiral dirhodium(II) carboxylate catalysts were identified using solution phase parallel synthesis techniques.