Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 63(18): 10188-10203, 2020 09 24.
Article in English | MEDLINE | ID: mdl-32407112

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacology , Hepatitis B, Chronic/drug therapy , Hexanols/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Toll-Like Receptor 8/agonists , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Crystallography, X-Ray , Dogs , Drug Discovery , Hepatitis B virus/drug effects , Hexanols/administration & dosage , Hexanols/chemical synthesis , Hexanols/metabolism , Humans , Macaca fascicularis , Molecular Structure , Protein Domains , Pyridines/administration & dosage , Pyridines/chemical synthesis , Pyridines/metabolism , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Rats , Structure-Activity Relationship , Toll-Like Receptor 8/metabolism
2.
Bioorg Med Chem ; 27(3): 457-469, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30606676

ABSTRACT

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.


Subject(s)
Benzimidazoles/pharmacology , Drug Discovery , Isoxazoles/pharmacology , Multiple Myeloma/drug therapy , Transcription Factors/antagonists & inhibitors , Administration, Oral , Animals , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Isoxazoles/administration & dosage , Isoxazoles/chemistry , Isoxazoles/metabolism , Mice , Molecular Structure , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Domains/drug effects , Structure-Activity Relationship , Transcription Factors/metabolism
3.
Bioorg Med Chem Lett ; 27(8): 1840-1847, 2017 04 15.
Article in English | MEDLINE | ID: mdl-28274633

ABSTRACT

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.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Nucleosides/chemistry , Nucleosides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antiviral Agents/pharmacokinetics , Caco-2 Cells , Cell Line , Cricetinae , Drug Discovery , Drug Resistance, Viral , Halogenation , Hepacivirus/genetics , Hepacivirus/physiology , Hepatitis C/drug therapy , Humans , Methylation , Molecular Docking Simulation , Nucleosides/pharmacokinetics , Phosphoric Acids/chemistry , Phosphoric Acids/pharmacokinetics , Phosphoric Acids/pharmacology , Point Mutation , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
4.
J Med Chem ; 57(5): 1812-25, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-23547794

ABSTRACT

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.


Subject(s)
Antiviral Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Hepacivirus/enzymology , Hepatitis C/drug therapy , Nucleosides/pharmacology , Organophosphorus Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Dogs , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Hepatitis C/enzymology , Hepatitis C/virology , Humans , Nucleosides/chemistry , Organophosphorus Compounds/chemistry , Rats , Viral Load
SELECTION OF CITATIONS
SEARCH DETAIL