Paola Zarantonello

Total synthesis and semi-synthetic approaches to analogues of antibacterial natural product althiomycin.

Numerous analogues of the naturally occurring antibiotic althiomycin have been synthesised exploiting both total- and semi-synthetic methodologies. The antibacterial activity of these derivatives has been determined in whole cell assays and indicates the natural product exhibits a restricted SAR.

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.

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.

Cyclopenta[d]pyrimidines and Dihydropyrrolo[2,3‐d]pyrimidines as Potent and Selective Corticotropin‐Releasing Factor 1 Receptor Antagonists

Two new classes of potent and selective CRF1 receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF1 antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF1 antagonists, as exemplified by compound 4 fi (4‐(4‐bromo‐3‐methyl‐1H‐pyrazol‐1‐yl)‐7‐(2,4‐dichlorophenyl)‐2‐methyl‐6,7‐dihydro‐5H‐pyrrolo[2,3‐d]pyrimidine), produced a dose‐dependent “anxiolytic‐like” effect when administered orally, decreasing the vocalization of rat pups.

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.

Heteroaryl-substituted 4-(1H-pyrazol-1-yl)-5,6-dihydro-1H-pyrrolo[2,3-d]pyrimidine derivatives as potent and selective corticotropin-releasing factor receptor-1 antagonists.

Heteroaryl-Substituted 4-(1H-pyrazol-1-yl)-5,6-dihydro-1H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent and Selective CorticotropinReleasing Factor Receptor-1 Antagonists Fabio Maria Sabbatini,* Romano Di Fabio,* Yves St-Denis, Anna-Maria Capelli, Emiliano Castiglioni, Stefania Contini, Daniele Donati, Elettra Fazzolari, Gabriella Gentile, Fabrizio Micheli, Francesca Pavone, Marilisa Rinaldi, Alessandra Pasquarello, Maria Grazia Zampori, Pina Di Felice, Paola Zarantonello, Roberto Arban, Benedetta Perini, Giovanni Vitulli, Roberto Benedetti, Beatrice Oliosi, and Angela Worby

The synthesis of 4-aminocarbonylmethoxy trinems

Abstract The synthesis of 4-aminocarbonylmethoxy trinems was accomplished through Lewis acid catalysed opening of an epoxide intermediate with allyl glycolate, followed by deallylation, activation of the free acid via the 2-pyridyl thiolester and reaction with a series of trimethylsilylamines. An alternative route involving a rhodium-catalysed diazoacetate insertion was also successfully exploited.