Ivan Leo Pinto

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.

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.

N-1 substituted pyrimidin-4-ones: Novel, orally active inhibitors of lipoprotein-associated phospholipase A2

From two related series of 2-(alkylthio)-pyrimidones, a novel series of 1-((amidolinked)-alkyl)-pyrimidones has been designed as nanomolar inhibitors of human lipoprotein-associated phospholipase A2. These compounds show greatly enhanced activity in isolated plasma. Selected derivatives such as compounds 51 and 52 are orally active with a good duration of action.

Non thiazolidinedione antihyperglycaemic agents. 2: α-Carbon substituted β-phenylpropanoic acids1

The thiazolidine-2,4-dione ring of insulin sensitising antidiabetic agents can be replaced by α-acyl-, α-alkyl- and α-(aralkyl)-carboxylic acids. Inclusion of an additional lipophilic moiety affords compounds 14 and 16, equipotent to BRL 48482.

natural product derived inhibitors of lipoprotein associated phospholipase a2, synthesis and activity of analogues of sb-253514

The synthesis of analogues of SB-253514, a novel natural product derived inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), is described together with their ability to inhibit Lp-PLA2.

Oxidation Adjacent to C X Bonds by Dehydrogenation

The synthetic versatility of α,β-unsaturated carbonyl compounds has resulted in the development of a wide variety of methods for their synthesis. Many such procedures rely on the construction of the basic carbon framework from simpler fragments, and are typified by reactions of the Wittig, Knoevenagel, aldol and Reformatsky type.1 To be able to introduce regioselective unsaturation into a previously established carbon skeleton is, however, an additional tool in the chemist’s armamentarium. In this review we have attempted to bring together the main literature relating to dehydrogenation methodology. No attempt has been made to include similar reactions that would generate alkynes or reactions that would result in the formation of carbon atoms doubly bonded to heteroatoms. Several of the intermediates described, and especially those involving α-selenenyl or α-thio moieties, offer the opportunity for further elaboration prior to elimination, since such species are able to stabilize adjacent carbanions.2–4 The synthetic applications arising from such intermediates are left to the ingenuity of the reader.