ABSTRACT
Crystallographic structural information was used in the design and synthesis of a number of bioisosteric derivatives to replace the amide moiety in a lead series of p38α inhibitors which showed general hydrolytic instability in human liver preparations. Triazole derivative 13 was found to have moderate bioavailability in the rat and demonstrated potent in-vivo activity in an acute model of inflammation.
Subject(s)
Amides/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Hydrogen Bonding , Indoles/chemistry , Indoles/pharmacokinetics , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
Subject(s)
Amides/chemistry , Aminobutyrates/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Structure-Activity Relationship , Amides/antagonists & inhibitors , Caco-2 Cells , Cell Line, Tumor , Chemistry, Pharmaceutical , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Design , Humans , Hypoglycemic Agents/antagonists & inhibitors , Hypoglycemic Agents/therapeutic use , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Sodium Channels/metabolismABSTRACT
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.
Subject(s)
Aminobutyrates/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Hydrocarbons, Fluorinated/chemistry , Hypoglycemic Agents/chemistry , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Administration, Oral , Aminobutyrates/chemical synthesis , Aminobutyrates/pharmacokinetics , Animals , Caco-2 Cells , Cell Line, Tumor , Dipeptidyl Peptidase 4/metabolism , Dogs , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.
Subject(s)
Amides/chemical synthesis , Aminobutyrates/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Microsomes, Liver/drug effects , Sulfonamides/chemical synthesis , Amides/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Glucagon-Like Peptide 1/antagonists & inhibitors , Hydrogen Bonding , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
4,5-Dihyroxypyrimidine carboxamides, which evolved from a related series of HCV NS5b polymerase inhibitors, have been optimized to provide selective HIV integrase strand transfer inhibitors. Extensive SAR around the benzylamide moiety led to the identification of the p-fluorobenzylamide as optimal in the enzymatic assay.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Amides/chemical synthesis , Amides/pharmacology , Hepacivirus/enzymology , Indicators and Reagents , Structure-Activity Relationship , Viral Nonstructural Proteins/antagonists & inhibitorsABSTRACT
The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
Subject(s)
Amides/chemical synthesis , HIV Integrase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Dogs , HIV Integrase Inhibitors/pharmacokinetics , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Humans , In Vitro Techniques , Macaca mulatta , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Rats , Serum , Structure-Activity Relationship , Virus ReplicationABSTRACT
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Hepacivirus/enzymology , Methylurea Compounds/chemical synthesis , Models, Molecular , Pyrimidines/chemical synthesis , Thiophenes/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/genetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Cell Line , Chelating Agents/chemistry , Crystallization , Humans , Methylurea Compounds/chemistry , Methylurea Compounds/pharmacology , Mutagenesis , Protein Conformation , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology , Viral Nonstructural Proteins/chemistry , Virus Replication/drug effectsABSTRACT
The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.
Subject(s)
Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Enzyme Inhibitors/chemistry , Phenethylamines , Animals , Binding Sites , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Molecular Structure , Phenethylamines/chemistry , Phenethylamines/metabolism , Proline/chemistry , Protein Binding , Structure-Activity Relationship , SwineABSTRACT
The design of a series of peptidomimetic inhibitors of the hepatitis C virus NS3 protease is described. These inhibitors feature an indoline-2-carboxamide as a novel heterocyclic replacement for the P3 amino acid residue and N-terminal capping group of tripeptide based inhibitors. The crystal structure of the ternary NS3/NS4A/inhibitor complex for the most active molecule in this series highlights its suitability as an N-terminal capping group of a dipeptide inhibitor of the NS3 protease.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Indoles/chemical synthesis , Oligopeptides/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Crystallography, X-Ray , Indoles/chemistry , Models, Molecular , Molecular Mimicry , Molecular Structure , Protein Binding , StereoisomerismABSTRACT
A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.
Subject(s)
Keto Acids/chemical synthesis , Pyrimidines/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Animals , Binding Sites , Drug Design , Hepacivirus/enzymology , In Vitro Techniques , Isomerism , Keto Acids/chemistry , Keto Acids/pharmacology , Microsomes, Liver/metabolism , Models, Molecular , Pyrimidines/chemistry , Pyrimidines/pharmacology , RNA-Dependent RNA Polymerase/chemistry , Rats , Structure-Activity RelationshipABSTRACT
SAR on the phenethylamide 1 (Ki 1.2 microM) in the P2- and the P'-position led to potent inhibitors, one of which showed good exposure and low clearance when administered intramuscularly to rat.
Subject(s)
Hepacivirus/enzymology , Phenethylamines/chemistry , Serine Endopeptidases/pharmacokinetics , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/pharmacokinetics , Animals , Hepacivirus/drug effects , Phenethylamines/pharmacology , Rats , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with alpha,gamma-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/drug effects , Hepacivirus/enzymology , Pyrones/chemistry , RNA, Viral/antagonists & inhibitors , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Binding Sites/physiology , Pyrones/metabolism , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase/metabolism , Viral Nonstructural Proteins/metabolismABSTRACT
The N-terminal aminoacid of phenethylamide tripeptide inhibitors of the hepatitis C virus NS3 protease can be replaced with an alpha-hydroxy acid to obtain more 'drug like' inhibitors with low micromolar activity. The preferred S-configuration of the capping residue can be explained by molecular modeling studies.
Subject(s)
Amides/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Models, Molecular , Protease Inhibitors/chemistryABSTRACT
alpha,gamma-Diketo acids (DKA) were discovered from screening as selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. The diketo acid moiety proved essential for activity, while substitution on the gamma position was necessary for selectivity and potency. Optimization led to the identification of a DKA inhibitor of NS5b polymerase with IC(50) = 45 nM, one of the most potent HCV NS5b polymerase inhibitors reported.
Subject(s)
Keto Acids/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/physiology , Keto Acids/chemistry , Models, Molecular , RNA-Dependent RNA Polymerase/chemistry , Structure-Activity RelationshipABSTRACT
Synthesis of hybrid HCV NS3 protease/NS4A inhibitors having the 4,4-difluoroaminobutyric acid (difluoroAbu) phenethylamides as P1-P1' and quinolyloxyprolines as P2 fragments led to 7 (IC(50) 54 nM). Molecular modelling suggests that this potent tripeptide inhibitor utilizes interactions in the S1', S1, S2, S3 and S4 sites of the protease.
Subject(s)
Aniline Compounds/chemical synthesis , Antiviral Agents/chemical synthesis , Hepacivirus/metabolism , Oligopeptides/chemical synthesis , Protease Inhibitors/chemical synthesis , Aminobutyrates/chemistry , Aniline Compounds/pharmacology , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepacivirus/genetics , Hydroquinones/chemistry , Hydroxyproline/chemistry , Models, Molecular , Oligopeptides/pharmacology , Protease Inhibitors/pharmacology , RNA Helicases , Serine Endopeptidases , Stereoisomerism , Structure-Activity Relationship , Viral Nonstructural ProteinsABSTRACT
The discovery of novel, reversible and competitive tripeptide inhibitors of the Hepatitis C virus NS3/4A serine protease is described. These inhibitors are characterized by the presence of a C-terminal phenethyl amide group, which extends into the prime side of the enzyme. Initial SAR together with molecular modeling and data from site-directed mutagenesis suggest an interaction of the phenethyl amide group with Lys-136.
Subject(s)
Amides/chemical synthesis , Benzene Derivatives/chemical synthesis , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Benzene Derivatives/chemistry , Models, Molecular , Protease Inhibitors/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
The N-terminal aminoacid of alpha-ketotripeptide inhibitors of the hepatitis C virus NS3 protease can be replaced with an alpha-hydroxy acid, leading to capped dipeptide inhibitors such as 20 with an IC(50) value of 3.0 microM. The importance of the lipophilic side chain interactions at S3 of the protease and the requirement of the capping residue with R configuration have been explained by molecular modeling studies.
Subject(s)
Dipeptides/pharmacology , Enzyme Inhibitors/chemical synthesis , Keto Acids/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Dipeptides/chemical synthesis , Enzyme Inhibitors/pharmacology , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity RelationshipABSTRACT
The difluoromethyl group was designed by computational chemistry methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor 4 (K(i) 30 nM) and reversible covalent inhibitors (6, K(i) 0.5 nM; and 8 K*(i) 10 pM).
Subject(s)
Cysteine , Hepacivirus/enzymology , Models, Molecular , Oligopeptides/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Drug Design , Humans , Molecular Mimicry , Oligopeptides/pharmacology , Structure-Activity RelationshipABSTRACT
N-terminal truncation of the hexapeptide ketoacid 1 gave rise to potent tripeptide inhibitors of the hepatitis C virus NS3 protease/NS4A cofactor complex. Optimization of these tripeptides led to ketoacid 30 with an IC50 of 0.38 microM. The SAR of these tripeptides is discussed in the light of the recently published crystal structures of a ternary tripetide/NS3/NS4A complexes.
