RESUMO
As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.
Assuntos
Fármacos Anti-HIV/química , HIV-1/metabolismo , Indóis/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Meia-Vida , Humanos , Indóis/síntese química , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Ligação Viral/efeitos dos fármacosRESUMO
PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.
Assuntos
Proteína Quinase C-alfa/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Ureia/síntese química , Ureia/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico , Cardiopatias/tratamento farmacológico , Humanos , Ureia/químicaRESUMO
The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Assuntos
Benzilaminas/química , Benzilaminas/farmacologia , Hormônio Paratireóideo/antagonistas & inibidores , Hormônio Paratireóideo/sangue , Receptores de Detecção de Cálcio/metabolismo , Administração Oral , Animais , Benzilaminas/administração & dosagem , Benzilaminas/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.