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1.
J Med Chem ; 64(7): 3658-3676, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33729773

RESUMO

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Proteínas Virais de Fusão/metabolismo
2.
J Med Chem ; 63(15): 8043-8045, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32786236

RESUMO

Inhibitors of the respiratory syncytial virus (RSV) fusion protein block entry of the virus into the cell and have shown varying efficacy in a human challenge model of RSV disease. Trials in patient populations are yet to show significant benefits. Jonckers et al. ( J. Med. Chem. 2020, DOI: 10.1021/acs.jmedchem.0c00226) describe the discovery of JNJ-53718678 which can now claim the leading position in clinical evaluation. For RSV inhibitors, the current status of the clinical development of the compound is discussed.


Assuntos
Antivirais/química , Imidazolidinas/química , Indóis/química , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Inibidores de Proteínas Virais de Fusão/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Cristalografia por Raios X/métodos , Humanos , Imidazolidinas/farmacologia , Imidazolidinas/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/fisiologia , Resultado do Tratamento , Inibidores de Proteínas Virais de Fusão/farmacologia
3.
J Med Chem ; 62(7): 3206-3227, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30411898

RESUMO

Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection.


Assuntos
Antivirais/química , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/química , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/metabolismo , Palivizumab/imunologia , Palivizumab/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/imunologia , Vírus Sincicial Respiratório Humano/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Proteínas Virais de Fusão/química , Proteínas Virais de Fusão/metabolismo
4.
J Med Chem ; 50(7): 1685-92, 2007 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-17341059

RESUMO

Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.


Assuntos
Antivirais/síntese química , Benzodiazepinas/síntese química , Benzodiazepinonas/síntese química , Compostos de Fenilureia/síntese química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacologia , Benzodiazepinonas/farmacocinética , Benzodiazepinonas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas In Vitro , Microssomos/metabolismo , Estrutura Molecular , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ensaio de Placa Viral
5.
J Med Chem ; 49(7): 2311-9, 2006 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-16570927

RESUMO

Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC(50)'s less than 50 muM. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.


Assuntos
Antivirais/síntese química , Benzodiazepinas/síntese química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Ensaio de Imunoadsorção Enzimática , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaio de Placa Viral
6.
Curr Top Med Chem ; 2(9): 1001-10, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12171567

RESUMO

This review covers literature describing research progress in erbB family tyrosine kinase inhibition over the last year. Excellent recent reviews are available, thus we have focussed on current developments of leading small molecule drug candidates as well as their erbB family inhibition profile. The most advanced erbB family tyrosine kinase (TK) inhibitors are demonstrating promising anti-cancer activity in clinical trials and are discussed. Several inhibition strategies are emerging: EGFR TK selective, irreversible TK inhibition and dual EGFR/erbB2 TK inhibitors. While small structural differences are seen in the leading compounds, the variations in their inhibition profiles and compound properties suggest that biological systems judge structural diversity differently. The readers' attention is drawn to common issues of selectivity and potency generally encountered with kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Oncogênicas v-erbB/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Ensaios Clínicos como Assunto , Humanos , Neoplasias/classificação , Neoplasias/enzimologia , Proteínas Oncogênicas v-erbB/classificação , Proteínas Oncogênicas v-erbB/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/classificação , Transdução de Sinais , Relação Estrutura-Atividade , Especificidade por Substrato
7.
Antimicrob Agents Chemother ; 51(9): 3346-53, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17576833

RESUMO

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.


Assuntos
Antivirais/farmacologia , Benzodiazepinonas/farmacologia , Compostos de Fenilureia/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Sequência de Aminoácidos , Antivirais/síntese química , Benzodiazepinonas/síntese química , Linhagem Celular , Fenômenos Químicos , Físico-Química , Efeito Citopatogênico Viral , Relação Dose-Resposta a Droga , Farmacorresistência Viral/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Mutação , Proteínas do Nucleocapsídeo/efeitos dos fármacos , Compostos de Fenilureia/síntese química , Vírus Sinciciais Respiratórios/genética , Sais de Tetrazólio , Replicação Viral/efeitos dos fármacos
8.
Bioorg Med Chem Lett ; 16(17): 4686-91, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16777410

RESUMO

Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.


Assuntos
Receptores ErbB/antagonistas & inibidores , Furanos/química , Furanos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Furanos/síntese química , Humanos , Concentração Inibidora 50 , Lapatinib , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 13(4): 637-40, 2003 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-12639547

RESUMO

We have identified a novel class of 6-thiazolylquinazolines as potent and selective inhibitors of both ErbB-2 and EGFR tyrosine kinase activity, with IC(50) values in the nanomolar range. These compounds inhibited the growth of both EGFR (HN5) and ErbB-2 (BT474) over-expressing human tumor cell lines in vitro. Using xenograft models of the same cell lines, we found that the compounds given orally inhibited in vivo tumor growth significantly compared with control animals.


Assuntos
Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Transplante Heterólogo
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