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Titolo:
Electrooxidation potential as a tool in the early screening for new safer clozapine-like analogues
Autore:
Mouithys-Mickalad, A; Kauffmann, JM; Petit, C; Bruhwyler, J; Liao, Y; Wikstrom, H; Damas, J; Delarge, J; Deby-Dupont, G; Geczy, J; Liegeois, JF;
Indirizzi:
Free Univ Brussels, Lab Instrumental Anal & Bioelectrochem, B-1050 Brussels, Belgium Free Univ Brussels Brussels Belgium B-1050 hem, B-1050 Brussels, Belgium Univ Liege, CORD, B-4000 Liege 1, Belgium Univ Liege Liege Belgium 1Univ Liege, CORD, B-4000 Liege 1, Belgium Therabel Res, B-1180 Brussels, Belgium Therabel Res Brussels Belgium B-1180 rabel Res, B-1180 Brussels, Belgium Univ Groningen, Dept Med Chem, NL-9713 AV Groningen, Netherlands Univ Groningen Groningen Netherlands NL-9713 AV V Groningen, Netherlands Univ Liege, Physiol Lab, B-4020 Liege, Belgium Univ Liege Liege Belgium B-4020 iege, Physiol Lab, B-4020 Liege, Belgium Univ Liege, Med Chem Lab, B-4000 Liege 1, Belgium Univ Liege Liege Belgium 1 Liege, Med Chem Lab, B-4000 Liege 1, Belgium
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 5, volume: 44, anno: 2001,
pagine: 769 - 776
SICI:
0022-2623(20010301)44:5<769:EPAATI>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
INDUCED AGRANULOCYTOSIS; APLASTIC-ANEMIA; PHARMACOLOGICAL PROPERTIES; REACTIVE METABOLITES; ANTIPSYCHOTIC-DRUGS; OXIDATION; SCHIZOPHRENIA; DERIVATIVES; OLANZAPINE; PYRIDOBENZOXAZEPINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Liegeois, JF Free Univ Brussels, Lab Instrumental Anal & Bioelectrochem, 205-6 Campus Plaine, B-1050 Brussels, Belgium Free Univ Brussels 205-6 Campus Plaine Brussels Belgium B-1050
Citazione:
A. Mouithys-Mickalad et al., "Electrooxidation potential as a tool in the early screening for new safer clozapine-like analogues", J MED CHEM, 44(5), 2001, pp. 769-776

Abstract

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b] [1,5]benzoxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, whendeveloping new derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The oxazepine derivative 7, unlike the other diazepine derivatives (6, 10-12), was not readily oxidized. Using a statistical predictivemodel for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH3O > CF3SO2O. The nature of the tricyclic ring influenced also the sensitivity tooxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 12:56:57