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1.
J Med Chem ; 59(13): 6086-100, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27299419

RESUMO

Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein. SMN2, a paralogous gene to SMN1, undergoes alternative splicing and exclusion of exon 7, producing an unstable, truncated SMNΔ7 protein. Herein, we report the identification of a pyridopyrimidinone series of small molecules that modify the alternative splicing of SMN2, increasing the production of full-length SMN2 mRNA. Upon oral administration of our small molecules, the levels of full-length SMN protein were restored in two mouse models of SMA. In-depth lead optimization in the pyridopyrimidinone series culminated in the selection of compound 3 (RG7800), the first small molecule SMN2 splicing modifier to enter human clinical trials.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Atrofia Muscular Espinal/tratamento farmacológico , Pirimidinonas/química , Pirimidinonas/farmacologia , RNA Mensageiro/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Animais , Éxons/efeitos dos fármacos , Humanos , Camundongos , Atrofia Muscular Espinal/genética , Pirimidinonas/farmacocinética , Pirimidinonas/uso terapêutico
2.
J Med Chem ; 59(13): 6070-85, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27299569

RESUMO

The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Atrofia Muscular Espinal/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linhagem Celular , Descoberta de Drogas , Éxons/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos Knockout , Atrofia Muscular Espinal/genética , RNA Mensageiro/genética , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Proteína 2 de Sobrevivência do Neurônio Motor/genética
3.
Bioorg Med Chem Lett ; 26(2): 594-601, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26652483

RESUMO

A novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides was identified and optimized for activity against the HCV genotype 1b replicon resulting in compounds with potent and selective activity. Further evaluation of this series demonstrated potent activity across HCV genotypes 1a, 2a and 3a. Compound 4z had reduced activity against HCV genotype 1b replicons containing single mutations in the NS4B coding sequence (F98C and V105M) indicating that NS4B is the target. This novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides serves as a promising starting point for a pan-genotype HCV discovery program.


Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Proteínas não Estruturais Virais/metabolismo , Sequência de Aminoácidos , Hepacivirus/química , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C/tratamento farmacológico , Humanos , Dados de Sequência Molecular , Mutação , Replicon/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética
4.
Bioorg Med Chem Lett ; 25(4): 781-6, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25613678

RESUMO

A structure-activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.


Assuntos
Hepacivirus/enzimologia , Piridinas/química , Piridinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacologia , Cães , Hepacivirus/efeitos dos fármacos , Humanos , Macaca fascicularis , Ratos , Relação Estrutura-Atividade
5.
Science ; 345(6197): 688-93, 2014 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-25104390

RESUMO

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Cumarínicos/administração & dosagem , Isocumarinas/administração & dosagem , Longevidade/efeitos dos fármacos , Atrofia Muscular Espinal/tratamento farmacológico , Pirimidinonas/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Administração Oral , Animais , Células Cultivadas , Cumarínicos/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Isocumarinas/química , Camundongos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Pirimidinonas/química , RNA Mensageiro/genética , Deleção de Sequência , Bibliotecas de Moléculas Pequenas/química , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
6.
J Med Chem ; 57(5): 2121-35, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24266880

RESUMO

A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC50 = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Cães , Haplorrinos , Humanos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética
7.
Bioorg Med Chem Lett ; 23(13): 3947-53, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23683597

RESUMO

A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Indóis/farmacologia , Piridinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Antivirais/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Hepacivirus/genética , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/genética
8.
Bioorg Med Chem Lett ; 23(13): 3942-6, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23683596

RESUMO

A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 µM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Indóis/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Sulfonamidas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Antivirais/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
9.
Nature ; 447(7140): 87-91, 2007 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-17450125

RESUMO

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.


Assuntos
Códon sem Sentido/genética , Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/genética , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Biossíntese de Proteínas/efeitos dos fármacos , Alelos , Animais , Disponibilidade Biológica , Distrofina/biossíntese , Distrofina/genética , Doenças Genéticas Inatas/sangue , Humanos , Camundongos , Camundongos Endogâmicos mdx , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacocinética , Fenótipo , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Especificidade por Substrato
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