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The family of phosphodiesterase (PDE) enzymes hydrolyse cyclic nucleotides, cAMP and cGMP, leading to their inactivation as intracellular second messengers. Inhibition of these enzymes leads to an elevation of levels of cyclic nucleotides in the cell and prolongs their action on downstream signaling pathways. PDE4, of which there are four subtypes, is widely expressed throughout the brain but is also abundant in the periphery in inflammatory and immune cells, in the gastrointestinal tract, and in cardiac myocytes. GSK356278 1 is a potent, selective, and competitive inhibitor of PDE4 enzymes currently under investigation for the treatment of CNS disorders. The initial synthetic route developed by Medicinal Chemistry Department, used several hazardous and/or expensive reagents and harsh conditions and gave relatively low yields. By targeted process of research and development plus application of analytical techniques to identify byproduct and extensive route scouting, a novel synthetic route for 1 has been developed. This contribution reports the optimisation of the chemical synthesis of 1 to develop a large-scale process suitable for its synthesis.

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1999 stereochemistry stereochemistry (general, optical resolution) O 0030 -036Enzymatic Method of Preparation of Optically Active trans-2-Aminocyclohexanol Derivatives.-Supported lipase PS-D catalyzes efficiently the resolution of protected trans-2-aminocyclohexanol (III) via a selective acylation reaction. -(URSINI, A.; MARAGNI, P.; BISMARA, C.; TAMBURINI, B.; Synth.

Using solution methods, we have synthesized several series of L‐methionine homooligopeptides from the dipeptide to the hexapeptide with either a free α‐carboxyl function or different C‐blocking groups (methoxy, benzyloxy, benzy‐lamino) and with N‐blocking groups of either the amide type (formyl, pivaloyl) or the urethane type (tert.‐butyloxycarbonyl). Compounds were compared to determine the combined effect of main‐chain length and presence and nature of N‐ and C‐blocking groups on conformation‐activity relationship. Each peptide was tested for its ability to induce rabbit peritoneal polymorphonuclear leukocytes in the presence of cytochalasin B to secrete granule enzymes. In parallel, a conformational analysis was carried out in the solid state and in solution, using infrared absorption and circular dichroism. The biological and conformational data are discussed in relation to a recently proposed model of the chemotactic peptide receptor of rabbit neutrophils.

Synthesis of Novel 6-α and 6-β-Alkylcarbonylmethyl Substituted Penems.-The antibacterial activity of novel title compounds (IV), (VII) is studied. 6-β-Alkylcarbonylmethyl penems are more active than the corresponding 6-α-analogues. Good activity is only achieved against Grampositive bacteria. -(PENTASSUGLIA, G.; TARZIA, G.; ANDREOTTI, D.; BISMARA, C.; CARLESSO, R.; DONATI, D.; GAVIRAGHI, G.; PERBONI, A.; PEZZOLI, A.; ROSSI, T.; TAMBURINI, B.; URSINI, A.; J.

Synthesis and Antimicrobial Activity of DNA-Gyrase Inhibiting Derivatives of 4-Oxo-1,4-dihydro-3-pyridinecarboxylic Acid.-Various 1-aryl-1,4-dihydropyridones are prepared. Particularly, arylvinyl substituted derivatives such as (IX) show high DNA-gyrase inhibiting activity. In the case of (IXb), this activity is combined with good antimicrobial properties. -(BASSINI, C.; BISMARA, C.; CARLESSO, R.; FERIANI, A.; GAVIRAGHI, G.; MARCHIORO, C.; PERBONI, A.; SHAW, R. E.; TAMBURINI, B.; TARZIA, G.; XERRI, L.; Farmaco, Ed.