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1.
Bioorg Med Chem Lett ; 27(18): 4323-4330, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28835346

ABSTRACT

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.


Subject(s)
Antiviral Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Uridine Monophosphate/analogs & derivatives , Uridine/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Liver/drug effects , Liver/virology , Mice , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine Monophosphate/chemical synthesis , Uridine Monophosphate/chemistry , Uridine Monophosphate/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
2.
Bioorg Med Chem Lett ; 25(22): 5427-36, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26410074

ABSTRACT

Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.


Subject(s)
Drug Discovery , Hepacivirus/drug effects , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Haplorhini , Hepatocytes/enzymology , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/enzymology , Molecular Structure , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry
3.
Bioorg Med Chem Lett ; 25(18): 3984-91, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26231161

ABSTRACT

We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Homoserine/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Hepacivirus/enzymology , Homoserine/chemical synthesis , Homoserine/chemistry , Microbial Sensitivity Tests , Molecular Structure , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
4.
Bioorg Med Chem Lett ; 25(6): 1212-6, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25701253

ABSTRACT

An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure-activity studies starting from 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063, 4) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties.


Subject(s)
Adenosine A2 Receptor Antagonists/chemical synthesis , Receptor, Adenosine A2A/chemistry , Thiazoles/chemical synthesis , para-Aminobenzoates/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/metabolism , Binding Sites , Humans , Ligands , Molecular Docking Simulation , Protein Binding , Receptor, Adenosine A2A/metabolism , Solubility , Structure-Activity Relationship , Thiazoles/chemistry , Water/chemistry , para-Aminobenzoates/chemistry
5.
Bioorg Med Chem Lett ; 24(18): 4444-4449, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25155387

ABSTRACT

Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic ß-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).


Subject(s)
Azetidines/pharmacology , Drug Design , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Azetidines/chemical synthesis , Azetidines/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
6.
Bioorg Med Chem Lett ; 14(15): 4027-30, 2004 Aug 02.
Article in English | MEDLINE | ID: mdl-15225720

ABSTRACT

Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC(50)=150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c.


Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Antipsychotic Agents/chemical synthesis , Piperazines/chemical synthesis , Piperazines/pharmacology , Acetates/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Antipsychotic Agents/therapeutic use , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Kinetics , Models, Molecular , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Rats , Receptors, N-Methyl-D-Aspartate/drug effects , Schizophrenia/drug therapy , Structure-Activity Relationship
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