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1.
Bioorg Med Chem Lett ; 28(10): 1954-1957, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29653894

RESUMO

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.


Assuntos
Antivirais/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Prolina/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Genótipo , Meia-Vida , Haplorrinos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/fisiologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Ratos , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
3.
Bioorg Med Chem Lett ; 26(20): 5132-5137, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27634194

RESUMO

Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.


Assuntos
Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos
5.
Bioorg Med Chem Lett ; 26(15): 3800-5, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27282742

RESUMO

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.


Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Hepatite C/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/química , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
6.
Bioorg Med Chem Lett ; 26(13): 3158-3162, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27180013

RESUMO

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Genótipo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
7.
ACS Med Chem Lett ; 7(3): 324-9, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985323

RESUMO

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

8.
Bioorg Med Chem Lett ; 26(5): 1475-9, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26850003

RESUMO

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.


Assuntos
Antivirais/química , Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Prolina/análogos & derivados , Silanos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Relação Dose-Resposta a Droga , Genótipo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Silanos/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
9.
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
10.
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
11.
Drug Metab Dispos ; 42(12): 2087-96, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25273356

RESUMO

Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of more than half of pharmaceutic drugs, and inactivation of CYP3A4 can lead to adverse drug-drug interactions. The substituted imidazole compounds 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine (SCH 66712) and 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP) have been previously identified as mechanism-based inactivators (MBI) of CYP2D6. The present study shows that both SCH 66712 and EMTPP are also MBIs of CYP3A4. Inhibition of CYP3A4 by SCH 66712 and EMTPP was determined to be concentration, time, and NADPH dependent. In addition, inactivation of CYP3A4 by SCH 66712 was shown to be unaffected by the presence of electrophile scavengers. SCH 66712 displays type I binding to CYP3A4 with a spectral binding constant (Ks) of 42.9 ± 2.9 µM. The partition ratios for SCH 66712 and EMTPP were 11 and 94, respectively. Whole protein mass spectrum analysis revealed 1:1 binding stoichiometry of SCH 66712 and EMTPP to CYP3A4 and a mass increase consistent with adduction by the inactivators without addition of oxygen. Heme adduction was not apparent. Multiple mono-oxygenation products with each inactivator were observed; no other products were apparent. These are the first MBIs to be shown to be potent inactivators of both CYP2D6 and CYP3A4.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Piperazinas/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Heme/metabolismo , Humanos , Imidazóis/farmacologia , Espectrometria de Massas , NADP/metabolismo , Piperazina , Piridinas/farmacologia , Pirimidinas/farmacologia
12.
Bioorg Med Chem Lett ; 24(4): 1228-31, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24462667

RESUMO

Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Piridinas/farmacologia , Alquil e Aril Transferases/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Haplorrinos , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
13.
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
14.
ChemMedChem ; 8(12): 1930-40, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24127258

RESUMO

The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.


Assuntos
Antivirais/química , Benzofuranos/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Imidazóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Benzofuranos/síntese química , Benzofuranos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Imidazóis/síntese química , Imidazóis/farmacocinética , Indóis/química , Mutação , Pan troglodytes , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
15.
Antimicrob Agents Chemother ; 57(7): 3250-61, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23629699

RESUMO

While new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug-resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC50) of 1.7 nM and an EC90 of 9.6 nM and demonstrated a >1,000-fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection.


Assuntos
Antivirais/metabolismo , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Indóis/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/metabolismo , Substituição de Aminoácidos , Animais , Antivirais/farmacocinética , Linhagem Celular Tumoral , Farmacorresistência Viral/genética , Sinergismo Farmacológico , Humanos , Indóis/metabolismo , Indóis/farmacocinética , Interferon-alfa/farmacologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
16.
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
17.
Int J Alzheimers Dis ; 2013: 823528, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23573456

RESUMO

Substantial evidence implicates ß-amyloid (Aß) peptides in the etiology of Alzheimer's disease (AD). Aß is produced by the proteolytic cleavage of the amyloid precursor protein by ß- and γ-secretase suggesting that γ-secretase inhibition may provide therapeutic benefit for AD. Although many γ-secretase inhibitors have been shown to be potent at lowering Aß, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another γ-secretase substrate. Here we describe the in vivo characterization of the novel γ-secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering Aß, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of Aß. However, additional studies revealed that both partial but sustained lowering of Aßand complete but less sustained lowering of Aß were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of Aß lowering by γ-secretase inhibitors, it is possible to obtain robust and sustained lowering of Aß without evidence of Notch-related side effects.

18.
Bioorg Med Chem Lett ; 23(3): 844-9, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23265892

RESUMO

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzopiranos/síntese química , Benzopiranos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Benzopiranos/química , Ciclização , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Relação Estrutura-Atividade , Sulfonas/química
19.
J Med Chem ; 55(1): 489-502, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-22098494

RESUMO

Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.


Assuntos
Amidinas/síntese química , Secretases da Proteína Precursora do Amiloide/metabolismo , Oxidiazóis/síntese química , Oxazinas/síntese química , Amidinas/farmacocinética , Amidinas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Cães , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Oxazinas/farmacocinética , Oxazinas/farmacologia , Fragmentos de Peptídeos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
20.
ACS Med Chem Lett ; 3(11): 892-6, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900404

RESUMO

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aß40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aß after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

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