title: Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies.
abstract: In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.
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: 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: 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: Fabio M
authors.initials: FM
authors.lastname: Sabbatini
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreotti
authors.forename: Simone
authors.initials: S
authors.lastname: Spada
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
authors.forename: Yves
authors.initials: Y
authors.lastname: St-Denis
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D000099052:CRF Receptor, Type 1
chemical_list: D008024:Ligands; D011725:Pyridines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1