RESUMO
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phaseâ 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
Assuntos
Inibidores de Proteases/química , Quinoxalinas/química , Valina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacocinética , Linhagem Celular , Cães , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Meia-Vida , Hepacivirus/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Inibidores de Proteases/farmacocinética , Quinoxalinas/síntese química , Quinoxalinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Valina/síntese química , Valina/química , Valina/farmacocinética , Proteínas não Estruturais Virais/metabolismoRESUMO
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Assuntos
Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Hepacivirus/metabolismo , Humanos , Ligação de Hidrogênio , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/química , Benzimidazóis/química , Imidazóis/síntese química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Concentração Inibidora 50 , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinética , Sulfonamidas/química , Sulfonamidas/farmacocinética , Administração Oral , Disponibilidade Biológica , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Hiperplasia Prostática/complicações , Pirimidinonas/farmacologia , Sulfonamidas/farmacologiaRESUMO
A series of aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in these new series. Several aryloxyazetidines also showed high levels of selectivity, with one compound, 25, displaying promising in vivo pharmacokinetics and significantly improved aqueous solubility over related compounds containing a biaryl substituent.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Azetidinas/química , Ocitocina/análogos & derivados , Triazóis/química , Administração Oral , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Cães , Humanos , Microssomos Hepáticos/metabolismo , Ocitocina/química , Ocitocina/farmacocinética , Ratos , Receptores de Vasopressinas/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinéticaRESUMO
The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
Assuntos
Piperazinas/síntese química , Piridazinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Animais , Cães , Desenho de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacologia , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Relação Estrutura-Atividade , Incontinência Urinária por Estresse/tratamento farmacológicoRESUMO
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Assuntos
Pirimidinonas/química , Pirimidinonas/uso terapêutico , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Pirimidinonas/farmacologia , Receptor 5-HT2B de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Uretra/efeitos dos fármacos , Incontinência Urinária/tratamento farmacológicoRESUMO
Several potent aryl ether/triazole oxytocin antagonists are described. The lead compound in this series had significantly improved aqueous solubility over related systems containing a biaryl substituent.
Assuntos
Ocitocina/antagonistas & inibidores , Triazóis/síntese química , Triazóis/farmacologia , Administração Oral , Animais , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
A novel series of Oxytocin antagonists are described. This series was identified through pharmacophoric overlap of in-house and literature antagonists. Subsequent optimization led to a series of potent, selective antagonists. Several analogues displayed oral bioavailability in vivo in the rat.