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1.
ACS Med Chem Lett ; 15(4): 546-554, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38628802

RESUMEN

Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.

2.
J Med Chem ; 63(18): 10188-10203, 2020 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-32407112

RESUMEN

Toll-like receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, (R)-7). Potent TLR8 agonism (IL-12p40 EC50 = 220 nM) and >100-fold TLR7 selectivity (IFN-α EC50 > 50 µM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:(R)-7 complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral (R)-7 had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with (R)-7, supporting the clinical development of (R)-7 for the treatment of CHB.


Asunto(s)
Antivirales/farmacología , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Receptor Toll-Like 8/agonistas , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/síntesis química , Antivirales/metabolismo , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Virus de la Hepatitis B/efectos de los fármacos , Hexanoles/administración & dosificación , Hexanoles/síntesis química , Hexanoles/metabolismo , Humanos , Macaca fascicularis , Estructura Molecular , Dominios Proteicos , Piridinas/administración & dosificación , Piridinas/síntesis química , Piridinas/metabolismo , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Ratas , Relación Estructura-Actividad , Receptor Toll-Like 8/metabolismo
3.
Bioorg Med Chem ; 27(3): 457-469, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30606676

RESUMEN

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.


Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas , Isoxazoles/farmacología , Mieloma Múltiple/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Administración Oral , Animales , Bencimidazoles/química , Bencimidazoles/metabolismo , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Isoxazoles/administración & dosificación , Isoxazoles/química , Isoxazoles/metabolismo , Ratones , Estructura Molecular , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Dominios Proteicos/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/metabolismo
4.
Bioorg Med Chem Lett ; 27(8): 1840-1847, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28274633

RESUMEN

A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/química , Nucleósidos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antivirales/farmacocinética , Células CACO-2 , Línea Celular , Cricetinae , Descubrimiento de Drogas , Farmacorresistencia Viral , Halogenación , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Humanos , Metilación , Simulación del Acoplamiento Molecular , Nucleósidos/farmacocinética , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacocinética , Ácidos Fosfóricos/farmacología , Mutación Puntual , Profármacos/química , Profármacos/farmacocinética , Profármacos/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
5.
Artículo en Inglés | MEDLINE | ID: mdl-26398773

RESUMEN

Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.


Asunto(s)
ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacología , Técnicas de Química Sintética , Inhibidores Enzimáticos/química , Nucleósidos de Pirimidina/química
6.
J Med Chem ; 57(5): 1812-25, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-23547794

RESUMEN

Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.


Asunto(s)
Antivirales/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Nucleósidos/farmacología , Compuestos Organofosforados/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Hepatitis C/enzimología , Hepatitis C/virología , Humanos , Nucleósidos/química , Compuestos Organofosforados/química , Ratas , Carga Viral
8.
Bioorg Med Chem Lett ; 19(4): 1187-90, 2009 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-19167883

RESUMEN

A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the 'halobenzyl tail' at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC(50) and t(1/2) in animal PK studies.


Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/química , Perros , Diseño de Fármacos , Inhibidores de Integrasa VIH/química , Humanos , Estructura Molecular , Pirroles/química , Quinolinas/química , Ratas , Relación Estructura-Actividad
10.
Bioorg Med Chem Lett ; 16(15): 3985-8, 2006 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16723226

RESUMEN

This communication details both the syntheses and biological evaluation of a novel class of HIV-1 integrase inhibitors. When the quinoline moiety is replaced with the quinoxoline moiety, the antiviral activity is significantly compromised. Similarly, introduction of imidazole to replace the pyridine ring is deleterious to the potency of the compound against the enzyme. Substitution at the 3-position of the pyridine has been investigated. The presence of the pyridine ring in the tricyclic core is preferred for antiviral activity against HIV integrase.


Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/efectos de los fármacos , Piridinas/química , Diseño de Fármacos , Inhibidores de Integrasa VIH/química , VIH-1/efectos de los fármacos
11.
Org Lett ; 5(12): 2095-8, 2003 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-12790537

RESUMEN

[reaction: see text] The asymmetric synthesis of a highly functionalized pentacyclic tetrahydroisoquinoline relevant to the ecteinascidin, saframycin, safracin, and renieramycin family of antitumor alkaloids is described.


Asunto(s)
Dioxoles/síntesis química , Isoquinolinas/síntesis química , Animales , Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/química , Dioxoles/química , Isoquinolinas/química , Modelos Moleculares , Estereoisomerismo , Tetrahidroisoquinolinas , Trabectedina , Urocordados/química
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