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1.
ACS Infect Dis ; 9(8): 1470-1487, 2023 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-37417544

RESUMO

Leishmaniasis is a collection of diseases caused by more than 20 Leishmania parasite species that manifest as either visceral, cutaneous, or mucocutaneous leishmaniasis. Despite the significant mortality and morbidity associated with leishmaniasis, it remains a neglected tropical disease. Existing treatments have variable efficacy, significant toxicity, rising resistance, and limited oral bioavailability, which necessitates the development of novel and affordable therapeutics. Here, we report on the continued optimization of a series of imidazopyridines for visceral leishmaniasis and a scaffold hop to a series of substituted 2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles with improved absorption, distribution, metabolism, and elimination properties.


Assuntos
Leishmania , Leishmaniose Visceral , Leishmaniose , Humanos , Leishmaniose Visceral/tratamento farmacológico , Doenças Negligenciadas , Imidazóis/farmacologia
2.
Drug Metab Lett ; 5(4): 280-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22022867

RESUMO

Rufinamide was evaluated in vitro to determine which enzyme(s) are responsible for rufinamide hydrolysis and whether valproate, one of its metabolites (valproyl-CoA), and/or the rufinamide hydrolysis product (CGP 47292) could inhibit hydrolysis. Rufinamide hydrolysis was mediated primarily by human carboxylesterase (hCE) 1 and was nonsaturable up to 500 µM. Two-thirds of rufinamide hydrolysis was estimated to occur in human microsomes and one-third in cytosol. Valproate was a selective inhibitor for hCE1 compared to hCE2 and inhibition had a greater impact on rufinamide hydrolysis in microsomes than in cytosol. Valproyl-CoA caused similar inhibition of rufinamide hydrolysis in both microsomes and cytosol. Carboxylesterases were not significantly inhibited by CGP 47292. Inhibition of in vitro rufinamide hydrolysis by valproate could offer an explanation for the observed in vivo drug-drug interaction between the two antiepileptic drugs.


Assuntos
Anticonvulsivantes , Carboxilesterase/antagonistas & inibidores , Inibidores Enzimáticos , Triazóis , Ácido Valproico , Acil Coenzima A/metabolismo , Acil Coenzima A/farmacologia , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Biotransformação , Butiratos/metabolismo , Carboxilesterase/metabolismo , Citosol/efeitos dos fármacos , Citosol/enzimologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrólise , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Triazóis/metabolismo , Triazóis/farmacologia , Ácido Valproico/metabolismo , Ácido Valproico/farmacologia
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