title: Cyclopenta[d]pyrimidines and dihydropyrrolo[2,3-d]pyrimidines as potent and selective corticotropin-releasing factor 1 receptor antagonists.
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-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.
authors.affiliation: GlaxoSmithKline Medicines Center, Psychiatry CEDD, Via A. Fleming 4, 37135 Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Arban
authors.forename: Roberto
authors.initials: R
authors.lastname: Benedetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bonanomi
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Capelli
authors.forename: Emiliano
authors.initials: E
authors.lastname: Castiglioni
authors.forename: Stefania
authors.initials: S
authors.lastname: Contini
authors.forename: Fabio
authors.initials: F
authors.lastname: Degiorgis
authors.forename: Pina
authors.initials: P
authors.lastname: Di Felice
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Elettra
authors.initials: E
authors.lastname: Fazzolari
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gentile
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchionni
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Flavia
authors.initials: F
authors.lastname: Messina
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oliosi
authors.forename: Francesca
authors.initials: F
authors.lastname: Pavone
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pasquarello
authors.forename: Benedetta
authors.initials: B
authors.lastname: Perini
authors.forename: Marilisa
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Sabbatini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitulli
authors.forename: Paola
authors.initials: P
authors.lastname: Zarantonello
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Yves
authors.initials: Y
authors.lastname: St-Denis
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014828:Vocalization, Animal / Q000187:drug effects; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1