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1.
Bioorg Med Chem Lett ; 27(15): 3294-3300, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28633899

RESUMEN

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Benzazepinas/química , Benzazepinas/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Benzazepinas/farmacocinética , Perros , Haplorrinos , Hepacivirus/enzimología , Hepacivirus/metabolismo , Hepatitis C/virología , Humanos , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Proteínas no Estructurales Virales/metabolismo
2.
J Med Chem ; 60(12): 5193-5208, 2017 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-28541707

RESUMEN

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Relación Estructura-Actividad , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Células CACO-2/efectos de los fármacos , Células CACO-2/inmunología , Perros , Canal de Potasio ERG1/metabolismo , Inhibidores Enzimáticos/química , Femenino , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Ratones Endogámicos BALB C , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Conejos
3.
J Med Chem ; 59(17): 8042-60, 2016 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-27564532

RESUMEN

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).


Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Isoquinolinas/uso terapéutico , Oligopéptidos/química , Sulfonamidas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/administración & dosificación , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Esquema de Medicación , Farmacorresistencia Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Conejos , Ratas Sprague-Dawley , Replicón , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico
4.
Eur J Med Chem ; 45(6): 2677-82, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20231043

RESUMEN

In the present investigation, a series of novel {5-chloro-2-[(3-(substitutedphenyl)-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanones (3a-i) have been synthesized from 5-(chloromethyl)-3-substitutedphenyl-1,2,4-oxadiazole (2a-i). The newly synthesized compounds were characterized by IR, NMR (1H and 13C), mass spectral and elemental analysis. The title compounds were investigated for in-vitro qualitative (zone of inhibition) and quantitative (MIC) antibacterial activity by agar cup plate and microtitration methods, respectively. The minimum inhibitory concentration and structure activity relationships (SARs) were evaluated. Amongst the synthesized compounds in this series, {5-chloro-2-[(3-(2,5-difluoro-4-methyl-phenyl)-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanone (3d) was found to exhibit significant activity with MICs of 21.5, 22.4, 29.8 and 30.6 microg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, respectively.


Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Benzofenonas/síntesis química , Benzofenonas/farmacología , Diseño de Fármacos , Antibacterianos/química , Bacterias/efectos de los fármacos , Benzofenonas/química , Espectroscopía de Resonancia Magnética
5.
Eur J Med Chem ; 44(11): 4522-7, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19640616

RESUMEN

In the present investigation a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles (4a-j) were synthesized by cyclization of substituted-benzoic acid N'-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hydrazide by using phosphorousoxychloride at 120 degrees C. The chemical structure of the newly synthesized compounds was characterized by analytical and spectral (IR, (1)H NMR, (13)C NMR and LC-MS) methods. The title compounds were screened for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup plate and microtitration methods, respectively. Among the synthesized compounds in this series compound 2-[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (4b) was found to exhibit significant antibacterial activity with MICs of 22.4, 29.8, 29.6 and 30.0 microg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, respectively. The other compounds exhibited moderate activity when compared to standard substance Ampicillin.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Oxadiazoles/química , Oxadiazoles/farmacología , Antibacterianos/síntesis química , Bacillus subtilis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Oxadiazoles/síntesis química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad
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