Identification of novel alpha7 nAChR positive allosteric modulators with the use of pharmacophore in silico screening methods.
The pharmacophore model of in house potent and selective alpha7 nAChR positive allosteric modulators is reported. The model was used to fish out commercially-available compounds from corporate 3D databases. As a result, novel alpha7 positive modulator chemotypes were identified. A rat full PK profile of a representative compound is also described.
Capelli
Anna Maria
AM
GlaxoSmithKline, Molecular Discovery Research, Verona, Italy. Anna-Maria.M.Capelli@gsk.com
Castelletti
Laura
L
Salvagno
Cristian
C
Oliosi
Beatrice
B
Di Lenarda
Elisa
E
Virginio
Caterina
C
Lightfoot
Andrew
A
Kew
James N C
JN
Teague
Simon
S
D000494:Allosteric Regulation; D000818:Animals; D002460:Cell Line; D016208:Databases, Factual; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007555:Isoxazoles; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor