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

✍ Scribed by Roberto Arban; Roberto Benedetti; Giorgio Bonanomi; Anna-Maria Capelli; Emiliano Castiglioni; Stefania Contini; Fabio Degiorgis; Pina Di Felice; Daniele Donati; Elettra Fazzolari; Gabriella Gentile; Chiara Marchionni; Carla Marchioro; Flavia Messina; Fabrizio Micheli; Beatrice Oliosi; Francesca Pavone; Alessandra Pasquarello; Benedetta Perini; Marilisa Rinaldi; Fabio M. Sabbatini; Giovanni Vitulli; Paola Zarantonello; Romano Di Fabio; Yves St-Denis

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 264 KB
• Volume: 2
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200600257

✦ Synopsis

Abstract

Two new classes of potent and selective CRF~1~ 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 CRF~1~ 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 CRF~1~ antagonists, as exemplified by compound 4 fi (4‐(4‐bromo‐3‐methyl‐1__H__‐pyrazol‐1‐yl)‐7‐(2,4‐dichlorophenyl)‐2‐methyl‐6,7‐dihydro‐5__H__‐pyrrolo[2,3‐d]pyrimidine), produced a dose‐dependent “anxiolytic‐like” effect when administered orally, decreasing the vocalization of rat pups.