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 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.
Arban
Roberto
R
GlaxoSmithKline Medicines Center, Psychiatry CEDD, Via A. Fleming 4, 37135 Verona, Italy.
Benedetti
Roberto
R
Bonanomi
Giorgio
G
Capelli
Anna-Maria
AM
Castiglioni
Emiliano
E
Contini
Stefania
S
Degiorgis
Fabio
F
Di Felice
Pina
P
Donati
Daniele
D
Fazzolari
Elettra
E
Gentile
Gabriella
G
Marchionni
Chiara
C
Marchioro
Carla
C
Messina
Flavia
F
Micheli
Fabrizio
F
Oliosi
Beatrice
B
Pavone
Francesca
F
Pasquarello
Alessandra
A
Perini
Benedetta
B
Rinaldi
Marilisa
M
Sabbatini
Fabio M
FM
Vitulli
Giovanni
G
Zarantonello
Paola
P
Di Fabio
Romano
R
St-Denis
Yves
Y
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
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1