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Cyclopenta[ d ]pyrimidines and Dihydropyrrolo[2,3‐ d ]pyrimidines as Potent and Selective Corticotropin‐Releasing Factor 1 Receptor Antagonists
Author(s) -
Arban Roberto,
Benedetti Roberto,
Bonanomi Giorgio,
Capelli AnnaMaria,
Castiglioni Emiliano,
Contini Stefania,
Degiorgis Fabio,
Di Felice Pina,
Donati Daniele,
Fazzolari Elettra,
Gentile Gabriella,
Marchionni Chiara,
Marchioro Carla,
Messina Flavia,
Micheli Fabrizio,
Oliosi Beatrice,
Pavone Francesca,
Pasquarello Alessandra,
Perini Benedetta,
Rinaldi Marilisa,
Sabbatini Fabio M.,
Vitulli Giovanni,
Zarantonello Paola,
Di Fabio Romano,
StDenis Yves
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600257
Subject(s) - chemistry , bioavailability , pyrimidine , pharmacokinetics , in vivo , anxiolytic , stereochemistry , metabolic stability , receptor , pharmacology , in vitro , biochemistry , biology , microbiology and biotechnology
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.