RESUMO
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Área Sob a Curva , Modelos Animais de Doenças , Hepacivirus/fisiologia , Hepatite C/virologia , Camundongos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologiaRESUMO
Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fenantrolinas/química , Fenantrolinas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Cães , Humanos , Modelos Moleculares , Fenantrolinas/síntese química , Fenantrolinas/farmacocinética , Ratos , Receptores CXCR4/metabolismoRESUMO
Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described.
Assuntos
Antivirais/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Antivirais/farmacologia , Linhagem Celular Tumoral , HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Modelos QuímicosRESUMO
Several novel amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines were synthesized which had potent activity against HIV-1. The synthetic approaches adopted allowed for variation of the substitution pattern and resulting changes in antiviral activity are highlighted. This led to the identification of compounds with low and sub-nanomolar anti-HIV-1 activity.
Assuntos
Aminas/química , Fármacos Anti-HIV/química , Benzimidazóis/química , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Aminas/síntese química , Aminas/farmacologia , Aminoquinolinas , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Butilaminas , Linhagem Celular Tumoral , Compostos Heterocíclicos com 1 Anel/química , Humanos , Receptores CXCR4/metabolismoRESUMO
The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.
Assuntos
Antivirais/química , Carbazóis/química , Papillomaviridae/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Carbazóis/farmacocinética , Carbazóis/toxicidade , Linhagem Celular , DNA Viral/efeitos dos fármacos , Feminino , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Cetonas/química , Cetonas/farmacocinética , Administração Oral , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/administração & dosagem , Humanos , Cetonas/administração & dosagem , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Assuntos
Amidas , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase , Cetonas , Pirrolidinas , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Sítios de Ligação , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/farmacocinética , Cetonas/farmacologia , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase , Relação Estrutura-AtividadeRESUMO
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Cetonas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Catepsina K , Catepsinas/química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Modelos Animais de Doenças , Hipocalcemia/tratamento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacologia , Ratos , Ratos Wistar , Solubilidade , Relação Estrutura-AtividadeRESUMO
Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.
Assuntos
Amidas/farmacologia , Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Sítios de Ligação , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Cinética , Conformação Proteica , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Sítios de Ligação , Catepsina K , Catepsinas/química , Humanos , Relação Estrutura-AtividadeRESUMO
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Catepsinas/antagonistas & inibidores , Administração Oral , Amidas/administração & dosagem , Animais , Disponibilidade Biológica , Catepsina K , Linhagem Celular , Cães , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Farmacocinética , Relação Estrutura-AtividadeRESUMO
A novel series of ketoamide-based inhibitors of cathepsin K has been identified. Modifications to P(2) and P(3) elements were crucial to enhancing inhibitory activity. Although not optimized, a selected inhibitor was effective in attenuating type I collagen hydrolysis in a surrogate assay of bone resorption.
Assuntos
Reabsorção Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Catepsinas/antagonistas & inibidores , Colágeno Tipo I/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Osso e Ossos/patologia , Catepsina K , Desenho de Fármacos , Humanos , Hidrólise , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.