RESUMO
Ziresovir (RO-0529, AK0529) is reported here for the first time as a promising respiratory syncytial virus (RSV) fusion (F) protein inhibitor that currently is in phase 2 clinical trials. This article describes the process of RO-0529 as a potent, selective, and orally bioavailable RSV F protein inhibitor and highlights the in vitro and in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays.
Assuntos
Antivirais/uso terapêutico , Benzazepinas/uso terapêutico , Quinazolinas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Tiazepinas/uso terapêutico , Proteínas Virais de Fusão/antagonistas & inibidores , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/síntese química , Antivirais/farmacocinética , Benzazepinas/administração & dosagem , Benzazepinas/síntese química , Benzazepinas/farmacocinética , Cães , Descoberta de Drogas , Feminino , Haplorrinos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/administração & dosagem , Quinazolinas/líquido cefalorraquidiano , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Ratos Wistar , Vírus Sincicial Respiratório Humano/química , Relação Estrutura-Atividade , Sulfonas , Tiazepinas/administração & dosagem , Tiazepinas/líquido cefalorraquidiano , Tiazepinas/farmacocinética , Proteínas Virais de Fusão/químicaRESUMO
A novel benzoazepinequnoline (BAQ) series was discovered as RSV fusion inhibitors. BAQ series originated from compound 2, a hit from similarity-based virtual screening. In SAR exploration, benzoazepine allowed modifications in the head moiety. Benzylic sulfonyl on benzoazepine and 6-Me on quinoline were crucial for good anti-RSV activity. Although the basic amine in the head portion was crucial for anti-RSV activity, the attenuated basicity was required to reduce Vss. Introducing oxetane to the head portion led to discovery of compound 1, which demonstrated single-digit nM anti-RSV activity against different RSV strains, reasonable oral exposure in plasma, and 78-fold higher exposure in lung. Compound 1 also displayed 1 log viral reduction in a female BALB/c mice RSV model by b.i.d. oral dosing at 12.5 mg/kg. A single resistant mutant at L138F in fusion protein proved compound 1 to be a RSV fusion inhibitor.
Assuntos
Antivirais/química , Antivirais/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Disponibilidade Biológica , Feminino , Células Hep G2 , Humanos , Camundongos , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.
Assuntos
Regulação Viral da Expressão Gênica/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Quinolinas/farmacologia , Quinolinas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Células Hep G2 , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/metabolismo , Humanos , Masculino , Camundongos , Fenótipo , Quinolinas/administração & dosagem , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Protein kinases play important roles in tumor development and progression. Lots of kinase inhibitors have entered into market and show promising clinical benefits. Here we report the discovery of a novel small molecule, well-tolerated, orally active kinase inhibitor, R1498, majorly targeting both angiogenic and mitotic pathways for the treatment of hepatocellular carcinoma (HCC) and gastric cancer (GC). A series of biochemical and cell-based assays indicated that the target kinase cluster of R1498 included Aurora kinases and VEGFR2 et al. R1498 showed moderate in vitro growth inhibition on a panel of tumor cells with IC50 of micromole range. The in vivo anti-tumor efficacy of R1498 was evaluated on a panel of GC and HCC xenografts in a parallel comparison with another multikinase inhibitor sorafenib. R1498 demonstrated superior efficacy and toxicity profile over sorafenib in all test models with >80% tumor growth inhibition and tumor regression in some xenogratfts. The therapeutic potential of R1498 was also highlighted by its efficacy on three human GC primary tumor derived xenograft models with 10-30% tumor regression rate. R1498 was shown to actively inhibit the Aurora A activity in vivo, and decrease the vascularization in tumors. Furthermore, R1498 presented good in vivo exposure and therapeutic window in the pharmacokinetic and dose range finding studies. Theses evidences indicate that R1498 is a potent, well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic and antiproliferative profile, and provide strong confidence for further development for HCC and GC therapy.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/metabolismo , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacocinética , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitose/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Ratos , Ratos Wistar , Transdução de Sinais , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/patologia , Carga Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC50 = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.