Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies.
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.
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
Arban
Roberto
R
Bernasconi
Giovanni
G
Braggio
Simone
S
Blaney
Frank E
FE
Capelli
Anna M
AM
Castiglioni
Emiliano
E
Donati
Daniele
D
Fazzolari
Elettra
E
Ratti
Emiliangelo
E
Feriani
Aldo
A
Contini
Stefania
S
Gentile
Gabriella
G
Ghirlanda
Damiano
D
Sabbatini
Fabio M
FM
Andreotti
Daniele
D
Spada
Simone
S
Marchioro
Carla
C
Worby
Angela
A
St-Denis
Yves
Y
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
D008024:Ligands; D011725:Pyridines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1