Alfredo Paio

Synthesis and pharmacological characterisation of 2,4-Dicarboxy-pyrroles as selective non-Competitive mGluR1 antagonists

Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.

Novel analogues of ketamine and phencyclidine as NMDA receptor antagonists.

The identification of structurally novel analogues of ketamine and phencyclidine (PCP), as NMDA receptor antagonists, with low to moderate potency at GluN2A and GluN2B receptors is discussed. In particular, some examples, such as compounds 6 and 10, shows decreased calculated lipophilicity, when compared to PCP, while retaining moderate activity. Moreover, the germinal aryl amino substituted lactam ring, as exemplified in compounds 7-10 and 11-13, constitutes a novel scaffold with potential application in the design of biologically active compounds.

Solid-Supported Nitrile Oxides as Stable and Valuable Reactive Intermediates

1,3-Dipolar cycloadditions of Wang resin supported nitrile oxides have been performed with several dipolarophiles to afford 5-membered heterocycles in fair yields. The nitrile oxides displayed increased stability on the solid phase, allowing clean transformations into nitrosocarbonyl intermediates, which could be trapped with suitable dienes to afford hetero Diels−Alder cycloadducts in moderate yields. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Phenylethynyl-pyrrolo[1,2-a]pyrazine: a new potent and selective tool in the mGluR5 antagonists arena.

The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.

Solid-phase versus solution synthesis of asymmetrically disubstituted furazano[3,4-b]pyrazines

Herein we describe a straightforward solid-phase synthesis directed towards the preparation of families of asymmetrically disubstituted furazano[3,4-b]pyrazines by stepwise displacement of the two chlorine atoms in 5,6-dichlorofurazano[3,4-b]pyrazine by nucleophiles. This synthesis has avoided selectivity problems found in solution chemistry.

Cyclative cleavage via solid-phase supported stabilized sulfur ylides: synthesis of macrocyclic lactones

A new synthesis of macrolactones bearing a cyclopropyl ring condensed to the macrocycle is reported via a cyclization-release strategy making use of solid-phase supported stabilized sulfur ylides.

New polymer-bound haloarene chromium dicarbonyl isocyanide complexes: a successful study validating their use in solid-phase chemistry

New fluorobenzene chromium dicarbonylisocyanide complexes have been synthesized and evaluated in terms of their ‘in solution’ reactivity towards some nucleophiles. For the first time the polymer-bound isocyanides have been found to be valuable ligands for anchoring haloareneCr(CO)3 complexes by means of their substitution for a CO group. The supported fluorobenzene complex reacted with nitrogen-nucleophiles.

Synthesis and pharmacological characterization of 5-phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-ones: a new class of Neuropeptide S antagonists.

A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.

Synthesis and Structure-Activity Relationships of α-Amino-γ-lactone Ketolides: A Novel Class of Macrolide Antibiotics.

An efficient synthesis of α-amino-γ-lactone ketolide (3) was developed, which provided a versatile intermediate for the incorporation of a variety of aryl and heteroaryl groups onto the C-21 position of clarithromycin via HBTU-mediated amidation. The biological data for this important new class of macrolides revealed significantly potent activity against erythromycin-susceptible strains as well as efflux-resistant and erythromycin MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted γ-lactone ketolides have potential as a next generation macrolide antibiotics.

Rapid Access to 1-Benzyl 2-Substituted Piperazines: Application to the Synthesis of 1-Benzyl-2-difluoromethyl-Piperazine

Abstract A rapid and efficient synthesis of 1-benzyl-2-difluoromethyl-piperazine is herein described. The new pathway has the advantage of avoiding orthogonal protection at the two piperazine nitrogen atoms; therefore it is suitable for access to several 1-benzyl 2-substituted piperazines starting from the simple commercially available N,N′-dibenzylethylendiamine.