Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Di Fabio
Romano
R
Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
St-Denis
Yves
Y
Sabbatini
Fabio M
FM
Andreotti
Daniele
D
Arban
Roberto
R
Bernasconi
Giovanni
G
Braggio
Simone
S
Blaney
Frank E
FE
Capelli
Anna M
AM
Castiglioni
Emiliano
E
Di Modugno
Enza
E
Donati
Daniele
D
Fazzolari
Elettra
E
Ratti
Emiliangelo
E
Feriani
Aldo
A
Contini
Stefania
S
Gentile
Gabriella
G
Ghirlanda
Damiano
D
Provera
Stefano
S
Marchioro
Carla
C
Roberts
Karen L
KL
Mingardi
Anna
A
Mattioli
Mario
M
Nalin
Arnaldo
A
Pavone
Francesca
F
Spada
Simone
S
Trist
David G
DG
Worby
Angela
A
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005552:Forelimb / Q000187:drug effects; D005849:Gerbillinae; D006801:Humans; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011581:Psychological Tests; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D014465:Ultrasonics; D014828:Vocalization, Animal / Q000187:drug effects; D000099052:CRF Receptor, Type 1
D011725:Pyridines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1