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Metabolism of an atypical antipsychotic agent, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone (HP236). 1996

A E Mutlib, and J Jurcak, and N Hrib
Neuroscience Product Group Unit, Hoechst-Roussel Pharmaceuticals, Inc.

Metabolism of an atypical antipsychotic agent, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone (HP236) by rats is described. HP236 was extensively metabolized both in vitro and in vivo. Metabolites were identified using electrospray interface-LC/MS (ESI-LC/MS) and 1H NMR spectroscopy. Protonated molecular ions, MH+, were observed for all the metabolites of HP236 using ESI-LC/MS. Tandem MS was performed on these quasimolecular ions to provide structural information. Structures of metabolites were confirmed by chromatographic and spectroscopic comparisons to synthetic standards. Metabolic pathways for HP236 both in vivo and in vitro included: a) cleavage of the thiazolidinone ring structure to give N-acetyl-N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]butyl]-2-methyl-propanamide, N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]-butyl]-2-methyl-propanamide, and N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]butyl]-acetamide; b) oxidation of the sulfide to give a mixture of sulfoxide diastereoisomers, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-1-oxo-2, 5,5-trimethyl-4-thiazolidinone and a sulfone, 1,1-dioxo-3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl ]-2, 5,5-trimethyl-4-thiazolidinone; and c) N-dealkylation at the piperazine ring to produce 3-(4-(1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone and 6-fluoro-3-(1-piperazinyl)benzo[b]thiophene. Metabolites found circulating in the plasma of rats dosed with HP236 were identical to those produced in vitro using rat liver microsomes or S9 fractions; however, LC/MS analysis of rat urine extract showed that the metabolite profile was different than that obtained from plasma or from in vitro extracts. The metabolite resulting from the cleavage of the thiazolidinone ring, N-acetyl-N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]-butyl]-2-methyl-propanamide, was the major circulating metabolite in the plasma of rats dosed with HP236. Results from in vitro studies showed that the metabolite was also produced by incubating the sulfoxides and sulfone analogs of HP236 with rat liver microsomes. A mechanism for the formation of N-acetyl-N-[4-[4-(6-fluorobenzo [b]thien-3-yl)-1-piperazinyl]butyl]-2-methyl-propanamide from HP236 is proposed.

UI MeSH Term Description Entries
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001711 Biotransformation The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.
D013058 Mass Spectrometry An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers. Mass Spectroscopy,Spectrometry, Mass,Spectroscopy, Mass,Spectrum Analysis, Mass,Analysis, Mass Spectrum,Mass Spectrum Analysis,Analyses, Mass Spectrum,Mass Spectrum Analyses,Spectrum Analyses, Mass
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D014150 Antipsychotic Agents Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. Antipsychotic,Antipsychotic Agent,Antipsychotic Drug,Antipsychotic Medication,Major Tranquilizer,Neuroleptic,Neuroleptic Agent,Neuroleptic Drug,Neuroleptics,Tranquilizing Agents, Major,Antipsychotic Drugs,Antipsychotic Effect,Antipsychotic Effects,Antipsychotics,Major Tranquilizers,Neuroleptic Agents,Neuroleptic Drugs,Tranquillizing Agents, Major,Agent, Antipsychotic,Agent, Neuroleptic,Drug, Antipsychotic,Drug, Neuroleptic,Effect, Antipsychotic,Major Tranquilizing Agents,Major Tranquillizing Agents,Medication, Antipsychotic,Tranquilizer, Major
D017208 Rats, Wistar A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain. Wistar Rat,Rat, Wistar,Wistar Rats
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

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