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4-AMINOPYRIDYL-BASED CYP51 INHIBITORS AS ANTI-TRYPANOSOMA CRUZI DRUG LEADS WITH IMPROVED PHARMACOKINETIC PROFILE AND IN VIVO POTENCY
Calvet, C. M. et al. | Data do documento: 2014
Autor(es)
Calvet, C. M.
Vieira, D. F.
Choi, J. Y.
Kellar, D.
Cameron, M. D.
Siqueira Neto, J. L.
Gut J.
Lin, L.
Khan S.
McKerrow, James H.
Roush, William R.
Podust, Larissa M.
Afiliação
University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. California, United States. Fundação Oswaldo Cruz. Laboratório de Ultraestrutura Celular.
University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. California, United States.
Department of Chemistry. Scripps Florida, Florida, United States
University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. California, United States.
Scripps Florida. Department of Molecular Therapeutics, Florida. United States.
University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. California, United States.
University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology.Department of Medicine. California. United States.
University of California San Francisco. Department of Pharmaceutical Chemistry. California, United States.
Scripps Florida. Department of Molecular Therapeutics. Florida, United States.
Scripps Florida. Department of Molecular Therapeutics. Florida, United States.
University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. California, United States.
Scripps Florida. Department of Chemistry. Florida, United States.
Scripps Florida. Department of Chemistry, Florida, United States. University of California. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. California, United States.
Resumo em Inglês
CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure−activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug−target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.
Palavras-chave
T. cruzi
quimioterapia
CYP51
 
DeCS
Ciências Biológicas
Editor
ACS Publications
Referência
CALVET, C. M.; et al. 4-aminopyridyl-based cyp51 inhibitors as anti-trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. Journal of Medicinal Chemistry, v.57, n.16, p. 6989-7005,2014.
DOI
DOI:10.1021/jm500448u
ISSN
00222623