No abstract

HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS) liability. The synthesis of these compounds, details of their structure-activity relationships, and discovery of a new lead, compound 50, as well as further development of the profiles of compounds 50 and 54 are described.

Structure-Activity Relationships of a Series of Novel ( Piperazinylbutyl)thiazolidinone Antipsychotic Agents Related to 3-(4-( 4-(6-Fluorobenzo(b)thien-3-yl)-1-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinone Maleate.-The title compound (Ib), isolated as maleate, displays a pharmacological profile indicative of potential atypical antipsychotic activity. A series (60 examples) of (piperazinylbutyl)thiazolidinones structurally related to (Ib) is prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds are examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect liability. Details of structureactivity relationships and the discovery of (Ia) as new lead compound are described. -(HRIB, N. J.; JURCAK, J. G.; BREGNA, D. E.; BURGHER, K. L.; HARTMANN, H. B.; KAFKA, S.; KERMAN, L. L.; KONGSAMUT, S.; ROEHR, J. E.; SZEWCZAK, M. R.; WOODS-KETTELBERGER, A. T.; CORBETT, R.; J.