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1.
Nat Chem ; 14(1): 15-24, 2022 01.
Article in English | MEDLINE | ID: mdl-34903857

ABSTRACT

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential ß-lactamase stable ß-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.


Subject(s)
beta-Lactamase Inhibitors/pharmacology , beta-Lactams/metabolism , Animals , Gram-Negative Bacteria/drug effects , Humans , Mice , Microbial Sensitivity Tests , Protein Binding , Structure-Activity Relationship , beta-Lactamase Inhibitors/chemistry , beta-Lactamase Inhibitors/metabolism
3.
Eur J Med Chem ; 148: 453-464, 2018 Mar 25.
Article in English | MEDLINE | ID: mdl-29477077

ABSTRACT

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on ß-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the ß-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM).


Subject(s)
Antiviral Agents/chemistry , Pyrazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Genotype , Hepacivirus/enzymology , Humans , Hydrogen Bonding , Protein Conformation, beta-Strand
4.
Bioorg Med Chem ; 24(12): 2603-20, 2016 06 15.
Article in English | MEDLINE | ID: mdl-27160057

ABSTRACT

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wild-type and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Pyrazines/chemistry , Pyrazines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Drug Resistance, Viral , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Molecular Docking Simulation , Point Mutation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/genetics
5.
J Med Chem ; 57(5): 1790-801, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-23517538

ABSTRACT

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 µM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.


Subject(s)
Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Hepacivirus/drug effects , Hepacivirus/enzymology , Magnetic Resonance Spectroscopy , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacokinetics , Stereoisomerism , Viral Nonstructural Proteins/metabolism
6.
Bioorg Med Chem Lett ; 22(9): 3265-8, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22472694

ABSTRACT

4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 µM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.


Subject(s)
Antiviral Agents/chemistry , Cytidine/analogs & derivatives , Deoxycytidine/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/pharmacology , Animals , Antiviral Agents/pharmacology , Cytidine/pharmacology , Deoxycytidine/pharmacology , Drug Discovery , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Rats , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects
7.
Bioorg Med Chem Lett ; 20(14): 4004-11, 2010 Jul 15.
Article in English | MEDLINE | ID: mdl-20541405

ABSTRACT

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Protease Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Area Under Curve , Caco-2 Cells , Humans , Intracellular Signaling Peptides and Proteins , Microsomes, Liver/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Structure-Activity Relationship
8.
J Med Chem ; 47(13): 3353-66, 2004 Jun 17.
Article in English | MEDLINE | ID: mdl-15189032

ABSTRACT

Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 microM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.


Subject(s)
Acrylonitrile/chemical synthesis , Antimalarials/chemical synthesis , Aspartic Acid Endopeptidases/antagonists & inhibitors , Dipeptides/chemical synthesis , Thiophenes/chemical synthesis , Acrylonitrile/analogs & derivatives , Acrylonitrile/chemistry , Acrylonitrile/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Aspartic Acid Endopeptidases/chemistry , Cathepsin D/antagonists & inhibitors , Cathepsin D/chemistry , Combinatorial Chemistry Techniques , Dipeptides/chemistry , Dipeptides/pharmacology , Humans , Models, Molecular , Molecular Mimicry , Plasmodium falciparum/drug effects , Protozoan Proteins , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology
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