| Author | Choi, Jun Yong | |
| Author | Calvet, Claudia M. | |
| Author | Gunatilleke, Shamila S. | |
| Author | Ruiz, Claudia | |
| Author | Cameron, Michael D. | |
| Author | McKerrow, James H. | |
| Author | Podust, Larissa M. | |
| Author | Roush, William R. | |
| Access date | 2017-01-24T15:03:38Z | |
| Available date | 2017-01-24T15:03:38Z | |
| Document date | 2013 | |
| Citation | CHOI, Jun Yong; et al. Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-Chagas agents. J Med Chem., v.56, n.19, :45p, 2013. | pt_BR |
| ISSN | 0022-2623 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/16917 | |
| Language | eng | pt_BR |
| Publisher | American Chemical Society | pt_BR |
| Rights | restricted access | |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Estrutura de raios-x | pt_BR |
| Subject in Portuguese | Inibidores de CYP51 | pt_BR |
| Title | Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents | pt_BR |
| Type | Article | |
| DOI | 10.1021/jm401067s | |
| Abstract | A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis. | pt_BR |
| Affilliation | Scripps Florida. Department of Chemistry. Florida, USA. | pt_BR |
| Affilliation | University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA / Fundação Oswaldo cruz. Instituto Oswaldo cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA / Seattle University. College of Scinece and Engineering. Seattle, WA, USA. | pt_BR |
| Affilliation | Scripps Florida. Department of Moleceular Therapeutics. Florida, USA. | pt_BR |
| Affilliation | Scripps Florida. Department of Moleceular Therapeutics. Florida, USA. | pt_BR |
| Affilliation | University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA. | pt_BR |
| Affilliation | University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. San Francisoo, CA, USA / University of California San Francisco. Department of Pathology. San Francisco, CA, USA. | pt_BR |
| Affilliation | Scripps Florida. Department of Chemistry. Florida, USA. | pt_BR |
| Subject | Chagas disease | pt_BR |
| Subject | non-azole CYP51 inhibitors | pt_BR |
| Subject | structure guided drug design | pt_BR |
| Subject | structure activity and property relationships | pt_BR |
| Subject | x-ray structure | pt_BR |
| e-ISSN | 1520-4804 | |
| Embargo date | 2030-01-01 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
