Benedetta Perini

Discovery Process and Characterization of Novel Carbohydrazide Derivatives as Potent and Selective GHSR1a Antagonists

Fabio Maria Sabbatini,* Romano Di Fabio,* Mauro Corsi, Paolo Cavanni, Steve M. Bromidge, Yves St-Denis, Lucilla D’Adamo, Stefania Contini, Marilisa Rinaldi, Sebastien Guery, Chiara Savoia, Claudia Mundi, Benedetta Perini, Andrew J. Carpenter, Giovanna Dal Forno, Federico Faggioni, Michela Tessari, Francesca Pavone, Carla Di Francesco, Alberto Buson, Mario Mattioli, Elisabetta Perdona’, and Sergio Melotto

Azabicyclo[3.1.0]hexane‐1‐carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior

Azabicyclo[3.1.0]hexane-1-carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior Fabio Maria Sabbatini,* Sergio Melotto, Giovanni Bernasconi, Steve M. Bromidge, Lucilla D’Adamo, Marilisa Rinaldi, Chiara Savoia, Claudia Mundi, Carla Di Francesco, Laura Zonzini, Vivian J. A. Costantini, Benedetta Perini, Enzo Valerio, Alfonso Pozzan, Elisabetta Perdon , Filippo Visentini, Mauro Corsi, and Romano Di Fabio*

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.

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