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1.
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
2.
Bioorg Med Chem ; 19(1): 145-55, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21183353

ABSTRACT

Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and ß-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19µM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Phenylbutyrates/pharmacology , Protease Inhibitors/pharmacology , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Mass Spectrometry , Phenylbutyrates/chemistry , Protease Inhibitors/chemistry
3.
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
4.
Bioorg Med Chem ; 18(4): 1711-23, 2010 Feb 15.
Article in English | MEDLINE | ID: mdl-20122837

ABSTRACT

In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Ethylenes/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet , Structure-Activity Relationship
5.
Bioorg Med Chem ; 16(21): 9471-86, 2008 Nov 01.
Article in English | MEDLINE | ID: mdl-18842420

ABSTRACT

Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.


Subject(s)
Amino Acids/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Design , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Crystallography, X-Ray , Humans , Models, Molecular , Peptide Fragments/chemical synthesis , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Protease Inhibitors/chemistry , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 18(18): 5095-100, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18722116

ABSTRACT

Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061, we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl)sulfonamide 19l an extremely potent (K(i)=0.20 nM, EC(50)=3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Carbamates/pharmacology , Macrocyclic Compounds/pharmacology , Quinolines/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Dogs , Liver/drug effects , Liver/metabolism , Molecular Structure , Rats , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemistry , Thiazoles/chemistry
7.
Bioorg Med Chem ; 15(22): 7184-202, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17845856

ABSTRACT

Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.


Subject(s)
Cyclopentanes/pharmacology , Enzyme Inhibitors/pharmacology , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Cell Line , Crystallography, X-Ray , Cyclization , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Dicarboxylic Acids/chemistry , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Humans , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Models, Molecular , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship , Virus Replication/drug effects
8.
Bioorg Med Chem ; 15(2): 827-38, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17107807

ABSTRACT

Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a K(i) value of 1.1nM.


Subject(s)
Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , Dicarboxylic Acids/chemical synthesis , Dicarboxylic Acids/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Indicators and Reagents , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Stereoisomerism , Structure-Activity Relationship
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