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1.
Pharm Res ; 21(11): 2079-84, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15587931

RESUMO

PURPOSE: The current study describes the design and validation of a novel oral vehicle for delivering poorly water-soluble herpes simplex virus (HSV)-helicase inhibitors in preclinical pharmacokinetic (PK) and pharmacodynamic (PD) evaluations. METHODS: Poorly water-soluble compounds were used in solubility and drinking compliance tests in mice. A preferred vehicle containing 0.1% bovine serum albumin (BSA), 3% dextrose, 5% polyethylene glycol (PEG) 400, and 2% peanut oil, pH 2.8 with HCL (BDPP) was selected. This vehicle was further validated with oral PK and in vivo antiviral PD studies using BILS 45 BS. RESULTS: Solubility screen and drinking compliance tests revealed that the BDPP vehicle could solubilize BILS compounds at 0.5-3 mg/ml concentration range and could be administered to mice without reducing water consumption. Comparative oral PK of BILS 45 BS in HCL or BDPP by gavage at 40 mg/kg showed overlapping PK profiles. In vivo antiviral efficacy and potency of BILS 45 BS in BDPP by oral gavages or in drinking water were confirmed to be comparable as that achieved by gavage in HCL solution. CONCLUSIONS: These results provide a protein-enriched novel oral vehicle for delivering poorly water-soluble antiviral compounds in a continuous administration mode. Similar approaches may be applicable to other poorly soluble compounds by gavage or in drinking solution.


Assuntos
DNA Helicases/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Simplexvirus/enzimologia , Aciclovir/administração & dosagem , Aciclovir/farmacocinética , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Fenômenos Químicos , Físico-Química , DNA Primase , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Excipientes , Feminino , Herpes Simples/patologia , Herpes Simples/prevenção & controle , Herpes Simples/virologia , Camundongos , Camundongos Pelados , Camundongos Nus , Veículos Farmacêuticos , Piridinas/administração & dosagem , Piridinas/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Proteínas Virais
2.
J Med Chem ; 47(7): 1605-8, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15027850

RESUMO

From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.


Assuntos
Antivirais/síntese química , Carbamatos/síntese química , Hepacivirus/enzimologia , Compostos Heterocíclicos/síntese química , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/química , Antivirais/farmacologia , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Injeções Intravenosas , Prolina/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade
3.
Antimicrob Agents Chemother ; 47(6): 1798-804, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12760851

RESUMO

This study investigated the oral bioavailability and efficacy of BILS 45 BS, a selective herpes simplex virus (HSV) helicase-primase inhibitor, against acyclovir (ACV)-resistant (ACV(r)) infections mediated by the HSV type 1 (HSV-1) dlsptk and PAA(r)5 mutant strains. In vitro, the compound was more potent than ACV against wild-type clinical and laboratory HSV-1 strains and ACV(r) HSV isolates, as determined by a standard plaque reduction assay, with a mean 50% effective concentration of about 0.15 microM. The oral bioavailability of BILS 45 BS in hairless mice was 49%, with a peak concentration in plasma of 31.5 microM after administration of a single dose of 25 mg/kg. Following cutaneous infection of nude mice, both the HSV-1 dlsptk and PAA(r)5 mutant strains induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. Oral treatment with ACV (100 or 125 mg/kg/day, three times a day by gavage) did not affect either mutant-induced infection. In contrast, BILS 45 BS at an oral dose of 100 mg/kg/day almost completely abolished cutaneous lesions mediated by both ACV(r) HSV-1 mutants. The 50% effective doses of BILS 45 BS were 56.7 and 61 mg/kg/day against dlsptk- and PAA(r)5-induced infections, respectively. Taken together, our results demonstrate very effective oral therapy of experimental ACV(r) HSV-1 infections in nude mice and support the potential use of HSV helicase-primase inhibitors for the treatment of nucleoside-resistant HSV disease in humans.


Assuntos
Antivirais/farmacologia , DNA Helicases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/crescimento & desenvolvimento , Piridinas/farmacologia , Tiazóis/farmacologia , Aciclovir/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , DNA Primase , Relação Dose-Resposta a Droga , Farmacorresistência Viral , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Camundongos , Camundongos Nus , Piridinas/administração & dosagem , Piridinas/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Proteínas Virais
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