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1.
Bioorg Med Chem Lett ; 23(12): 3487-90, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23664214
3.
J Med Chem ; 61(3): 1153-1163, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29342358

RESUMO

ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.


Assuntos
Citosina/análogos & derivados , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Estilbenos/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Técnicas de Química Sintética , Citosina/síntese química , Citosina/química , Citosina/farmacocinética , Citosina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Permeabilidade , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribuição Tecidual , Proteínas não Estruturais Virais/química
4.
J Med Chem ; 57(5): 2047-57, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24400777

RESUMO

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.


Assuntos
Anilidas/farmacologia , Antivirais/farmacologia , Carbamatos/farmacologia , Genótipo , Hepacivirus/efeitos dos fármacos , Sulfonamidas/farmacologia , Uracila/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , 2-Naftilamina , Anilidas/química , Anilidas/farmacocinética , Animais , Antivirais/química , Antivirais/farmacocinética , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacocinética , Linhagem Celular , Descoberta de Drogas , Hepacivirus/enzimologia , Humanos , Prolina , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinética , Uracila/química , Uracila/farmacocinética , Uracila/farmacologia , Valina
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