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.
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.
Hrib
N J
NJ
Neuroscience Therapeutic Area, Hoechst Marion Roussel, Inc., Bridgewater, New Jersey 08876, USA.
Jurcak
J G
JG
Bregna
D E
DE
Burgher
K L
KL
Hartman
H B
HB
Kafka
S
S
Kerman
L L
LL
Kongsamut
S
S
Roehr
J E
JE
Szewczak
M R
MR
Woods-Kettelberger
A T
AT
Corbett
R
R
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D053778:Thiazolidines
C101733:3-(4-(4-(6-fluorobenzo(b)thiophene-3-yl)-1-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro(4.4)nonan-4-one; D014150:Antipsychotic Agents; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D013141:Spiro Compounds; D013844:Thiazoles; D053778:Thiazolidines; C075804:HP 236; D050638:Receptors, Dopamine D4; D013134:Spiperone; D001058:Apomorphine