Studies towards the identification of a new generation of atypical antipsychotic agents.
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Garzya
Vincenzo
V
Psychiatry Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK. Vincenzo_2_garzya@gsk.com
Forbes
Ian T
IT
Gribble
Andrew D
AD
Hadley
Mike S
MS
Lightfoot
Andrew P
AP
Payne
Andrew H
AH
Smith
Alexander B
AB
Douglas
Sara E
SE
Cooper
David G
DG
Stansfield
Ian G
IG
Meeson
Malcom
M
Dodds
Emma E
EE
Jones
Declan N C
DN
Wood
Martyn
M
Reavill
Charlie
C
Scorer
Carol A
CA
Worby
Angela
A
Riley
Graham
G
Eddershaw
Peter
P
Ioannou
Chris
C
Donati
Daniele
D
Hagan
Jim J
JJ
Ratti
Emiliangelo A
EA
D000478:Alkylation; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D006801:Humans; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors; D011985:Receptors, Serotonin / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor; D003577:Cytochrome P-450 Enzyme System