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Studies towards the identification of a new generation of atypical antipsychotic agents.

Garzya, Vincenzo; Forbes, Ian T; Gribble, Andrew D; Hadley, Mike S; Lightfoot, Andrew P; Payne, Andrew H; Smith, Alexander B; Douglas, Sara E; Cooper, David G; Stansfield, Ian G; Meeson, Malcom; Dodds, Emma E; Jones, Declan N C; Wood, Martyn; Reavill, Charlie; Scorer, Carol A; Worby, Angela; Riley, Graham; Eddershaw, Peter; Ioannou, Chris; Donati, Daniele; Hagan, Jim J; Ratti, Emiliangelo A.

Bioorg Med Chem Lett ; 17(2): 400-5, 2007 Jan 15.

Article in English | MEDLINE | ID: mdl-17084080

ABSTRACT

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.

Subject(s)

Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Alkylation , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Drug Design , Humans , Receptor, Serotonin, 5-HT2A/drug effects , Receptor, Serotonin, 5-HT2C/drug effects , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Serotonin/drug effects , Recombinant Proteins/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology

ABSTRACT

Subject(s)

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