title: 7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics.
abstract: Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bioavailability. These variations included a series of piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further optimization of these structures led to the highly potent 7-[3-(1-piperidinyl)propoxy]chromenones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher than required for inhibition of climbing suggest an atypical antipsychotic profile, which is assumed to predict a reduced induction of extrapyramidal side effects in humans.
authors.affiliation: Department of Medicinal Chemistry, Centro de Investigación Grupo Ferrer, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Bolós
authors.forename: S
authors.initials: S
authors.lastname: Gubert
authors.forename: L
authors.initials: L
authors.lastname: Anglada
authors.forename: J M
authors.initials: JM
authors.lastname: Planas
authors.forename: C
authors.initials: C
authors.lastname: Burgarolas
authors.forename: J M
authors.initials: JM
authors.lastname: Castelló
authors.forename: A
authors.initials: A
authors.lastname: Sacristán
authors.forename: J A
authors.initials: JA
authors.lastname: Ortiz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D002375:Catalepsy / Q000139:chemically induced; D002867:Chromones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C100734:3-hydroxymethyl-7-(3-(4-(4-fluorobenzoyl)-1-piperidinyl)propoxy)chromen-4-one; C100733:3-methyl-7-(3-(4-(4-fluorobenzoyl)-1-piperidinyl)propoxy)chromen-4-one; C100732:7-(3-(4-(4-fluorobenzoyl)-1-piperidinyl)propoxy)chromen-4-one; D014150:Antipsychotic Agents; D002867:Chromones; D001058:Apomorphine