title: Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.
abstract: 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.
authors.affiliation: 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
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Yves
authors.initials: Y
authors.lastname: St-Denis
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Sabbatini
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreotti
authors.forename: Roberto
authors.initials: R
authors.lastname: Arban
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bernasconi
authors.forename: Simone
authors.initials: S
authors.lastname: Braggio
authors.forename: Frank E
authors.initials: FE
authors.lastname: Blaney
authors.forename: Anna M
authors.initials: AM
authors.lastname: Capelli
authors.forename: Emiliano
authors.initials: E
authors.lastname: Castiglioni
authors.forename: Enza
authors.initials: E
authors.lastname: Di Modugno
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Elettra
authors.initials: E
authors.lastname: Fazzolari
authors.forename: Emiliangelo
authors.initials: E
authors.lastname: Ratti
authors.forename: Aldo
authors.initials: A
authors.lastname: Feriani
authors.forename: Stefania
authors.initials: S
authors.lastname: Contini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gentile
authors.forename: Damiano
authors.initials: D
authors.lastname: Ghirlanda
authors.forename: Stefano
authors.initials: S
authors.lastname: Provera
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Karen L
authors.initials: KL
authors.lastname: Roberts
authors.forename: Anna
authors.initials: A
authors.lastname: Mingardi
authors.forename: Mario
authors.initials: M
authors.lastname: Mattioli
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Nalin
authors.forename: Francesca
authors.initials: F
authors.lastname: Pavone
authors.forename: Simone
authors.initials: S
authors.lastname: Spada
authors.forename: David G
authors.initials: DG
authors.lastname: Trist
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
mesh_terms: 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
chemical_list: D011725:Pyridines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1