RESUMO
We report a new series of inhibitors for hepatitis C virus NS5B RNA polymerase containing a constrained pentacyclic scaffold. Our SAR studies led to the identification of hexahydroindolo[2,1-a]pyrrolo[3,2-d][2]benzazepines exposing basic groups. The compounds displayed a high activity in the enzyme assay and displayed good activity in the cell-based (replicon) assay in the presence of serum proteins.
Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Benzazepinas/química , RNA Polimerases Dirigidas por DNA/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Fígado/virologia , Modelos Químicos , Modelos Moleculares , Conformação Molecular , RNA Viral/genética , Relação Estrutura-AtividadeRESUMO
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
Assuntos
Inibidores de Integrase de HIV/síntese química , Integrase de HIV/química , HIV-1/efeitos dos fármacos , Morfolinas/síntese química , Pirimidinonas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Cães , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/farmacologia , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Macaca mulatta , Morfolinas/farmacocinética , Morfolinas/farmacologia , Ligação Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Indóis/síntese química , Oxazocinas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Macaca mulatta , Camundongos , Camundongos SCID , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Oxazocinas/farmacocinética , Oxazocinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Viremia/tratamento farmacológico , Viremia/virologia , Replicação Viral/efeitos dos fármacosRESUMO
A short efficient enantioselective synthesis of both (+)- and (-)-saudin, a naturally occurring hypoglycemic diterpene, is described. This synthesis establishes the absolute configuration of natural (-)-saudin for the first time. The key steps include the enantioselective construction of a dimethyl Hagemann's ester by an asymmetric Michael reaction and establishment of the key 1,3 disposed quaternary centers by means of a novel Ti(IV) promoted Claisen rearrangement. The assembly of the polycyclic ketal skeleton was likely under kinetic control proceeding via formation of the C1oxygen-C7 bond through an oxonium ion intermediate in the final stage.