ABSTRACT
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Nitrogen/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Sulfur/chemistry , Thiazoles/chemistry , Binding Sites , Crystallography, X-Ray , Drug Design , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
AIM: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney. METHODS: Unilateral ureteric obstruction was induced in C57BL/6J mice which then received an ERK inhibitor drug (U0126 100 mg/kg t.i.d.), vehicle (DMSO) or no treatment, starting at day 2 after unilateral ureteric obstruction surgery and continuing until animals were killed on day 5. Cell proliferation was assessed by uptake of bromodeoxyuridine (BrdU). RESULTS: In normal mice, phosphorylation (activation) of ERK (p-ERK) was restricted to collecting ducts. Western blotting identified a marked increase in p-ERK in the obstructed kidney in the no-treatment and vehicle-treated groups. Immunostaining showed strong p-ERK staining in many tubules and in interstitial cells. U0126 treatment inhibited ERK phosphorylation as assessed by western blot and immunostaining. The number of BrdU+ cortical tubular cells was reduced by vehicle treatment but was not further changed by U0126 treatment. In contrast, interstitial cell proliferation in the obstructed kidney was unaltered by vehicle treatment, but this was significantly inhibited by U0126. This was associated with a reduction in interstitial macrophage accumulation, but no effect was seen upon interstitial accumulation of alpha-SMA+ myofibroblasts. Renal fibrosis, as assessed by collagen deposition, was unaffected by U0126 or vehicle treatment. CONCLUSION: These studies show that accumulation of interstitial macrophages in the obstructed kidney is, in part, dependent upon the ERK signalling pathway.
Subject(s)
Kidney Diseases/enzymology , Mitogen-Activated Protein Kinase Kinases/metabolism , Signal Transduction , Animals , Butadienes/administration & dosage , Butadienes/pharmacology , Cell Proliferation/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , Nitriles/administration & dosage , Nitriles/pharmacology , Ureteral Obstruction/surgeryABSTRACT
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Benzamides/chemistry , Benzamides/pharmacology , ADAM17 Protein , Animals , Area Under Curve , Benzamides/blood , Benzamides/pharmacokinetics , Biological Availability , Dogs , Half-Life , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Alkanes/chemistry , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Spiro Compounds/chemistry , ADAM17 Protein , Administration, Oral , Alkanes/chemical synthesis , Alkanes/pharmacokinetics , Alkanes/pharmacology , Animals , Biological Availability , Caco-2 Cells , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Matrix Metalloproteinases/metabolism , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacologyABSTRACT
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
Subject(s)
Benzothiazoles/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Animals , Cells, Cultured/drug effects , Cells, Cultured/enzymology , Crystallography, X-Ray , Humans , Lipopolysaccharides/pharmacology , Mice , Microsomes/drug effects , Microsomes/enzymology , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Benzofurans/chemistry , Imidazoles/chemistry , Indoles/chemistry , Protease Inhibitors/pharmacology , Pyrazoles/chemistry , Pyridines/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Administration, Oral , Animals , Biological Availability , Humans , Hydroxamic Acids/chemistry , Lipopolysaccharides/pharmacology , Matrix Metalloproteinase Inhibitors , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , ADAM Proteins/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Administration, Oral , Animals , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/pharmacology , Binding Sites , Biological Availability , Dogs , Hydroxamic Acids/pharmacokinetics , Models, Molecular , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , SwineABSTRACT
BACKGROUND: In vitro, the extracellular signal-regulated kinase (ERK) is an intracellular convergence point of multiple stimuli, which affect the cell cycle. However, the role of ERK in cell cycle regulation in vivo is unknown. METHODS: To address this issue, ERK activity was blocked both in vitro in mesangial cells (MC) and in vivo in experimental glomerulonephritis (GN) by a pharmacological inhibitor (U0126) of the ERK-activating kinase. RESULTS: In stimulated MC, inhibition of ERK reduced cyclin-dependent kinase 2 (CDK2) phosphorylation, CDK2 activity and cyclin E/A expression, whereas downregulation of CDK inhibitor p27(Kip1) expression was inhibited. In vivo, U0126 was given to rats in the acute phase of anti-Thy 1.1 GN. We previously showed that glomerular cell proliferation was reduced by 67% upon treatment with the inhibitor compared to nephritic controls. Now, we detected a significant increase in renal CDK2-activity/phosphorylation in the nephritic controls, that was significantly and dose-dependently reduced by ERK inhibition. CDK2 activation was accompanied by an increase in renal expression of cyclins E/A and the enhanced binding of these cyclins to CDK2 in the nephritic controls. These changes were blunted by U0126 treatment. Finally, we noted an increased expression and CDK2-binding of p27(KIP1) protein in the nephritic controls which was decreased in U0126 treated rats. CONCLUSIONS: Our observations provide the first evidence that ERK is an intracellular regulator of renal CDK2 activity in vivo in a glomerulonephritis model.
Subject(s)
Cyclin-Dependent Kinase 2/metabolism , Extracellular Signal-Regulated MAP Kinases/physiology , Glomerulonephritis/enzymology , Animals , Cells, Cultured , Glomerular Mesangium/cytology , Glomerular Mesangium/metabolism , Male , Rats , Rats, WistarABSTRACT
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Endotoxemia/drug therapy , Quinolines/pharmacokinetics , Quinolines/therapeutic use , ADAM17 Protein , Adult , Animals , Anti-Inflammatory Agents/blood , Arthritis, Experimental/blood , Arthritis, Experimental/pathology , Dogs , Double-Blind Method , Endotoxemia/blood , Endotoxemia/chemically induced , Female , Humans , Lipopolysaccharides , Male , Mice , Mice, Inbred BALB C , Pan troglodytes , Quinolines/blood , Rats , Rats, Inbred Strains , Synovial Fluid/chemistry , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/bloodABSTRACT
Once-daily s.c. administration of either human parathyroid hormone (PTH)-(1-84) or recombinant human PTH-(1-34) provides for dramatic increases in bone mass in women with postmenopausal osteoporosis. We initiated a program to discover orally bioavailable small molecule equivalents of these peptides. A traditional high-throughput screening approach using cAMP activation of the PTH/PTH-related peptide receptor (PPR) as a readout failed to provide any lead compounds. Accordingly, we designed a new screen for this receptor that used a modified N-terminal fragment of PTH as a probe for small molecule binding to the transmembrane region of the PPR, driven by the assumption that the pharmacological properties (agonist/antagonist) of compounds that bound to this putative signaling domain of the PPR could be altered by chemical modification. We developed DPC-AJ1951, a 14 amino acid peptide that acts as a potent agonist of the PPR, and characterized its activity in ex vivo and in vivo assays of bone resorption. In addition, we studied its ability to initiate gene transcription by using microarray technology. Together, these experiments indicated that the highly modified 14 amino acid peptide induces qualitatively similar biological responses to those produced by PTH-(1-34), albeit with lower potency relative to the parent peptide. Encouraged by these data, we performed a screen of a small compound collection by using DPC-AJ1951 as the ligand. These studies led to the identification of the benzoxazepinone SW106, a previously unrecognized small molecule antagonist for the PPR. The binding of SW106 to the PPR was rationalized by using a homology receptor model.
Subject(s)
Molecular Probes/physiology , Oxazepines/pharmacology , Parathyroid Hormone/physiology , Peptide Fragments/physiology , Receptor, Parathyroid Hormone, Type 1/antagonists & inhibitors , Amino Acid Sequence , Animals , Binding, Competitive , Cell Line , Drug Evaluation, Preclinical , Humans , Male , Molecular Probe Techniques , Molecular Sequence Data , Oxazepines/agonists , Parathyroid Hormone/agonists , Parathyroid Hormone/metabolism , Peptide Fragments/agonists , Peptide Fragments/metabolism , Protein Binding , Rats , Rats, Sprague-Dawley , Receptor, Parathyroid Hormone, Type 1/agonists , Receptor, Parathyroid Hormone, Type 1/metabolismABSTRACT
A new P1' group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1' group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different beta-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole blood activity, excellent PK properties, and good selectivity against a variety of MMPs.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Hydroxamic Acids/chemistry , ADAM Proteins/blood , ADAM17 Protein , Animals , Dogs , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Oxygen/chemistry , Rats , Structure-Activity Relationship , SwineABSTRACT
CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EPhi), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of EPhi recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.p. injections of ovalbumin (OVA), and the effects were monitored by bronchoalveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of EPhi was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of EPhi, the effect of eotaxin in OVA-sensitized mice was not a direct chemotactic stimulus because mast cell deficiency (in WBB6F1-Kitw/Kitw-v mice) significantly reduced the response. Two representative small molecule CCR3 antagonists from our program were characterized as being active at mouse CCR3. They were administered p.o. to wild-type mice and found to reduce eotaxin-elicited EPhi selectively in a dose-dependent manner. Pump infusion of one of the inhibitors to achieve steady-state levels showed that efficacy was not achieved at plasma concentrations equivalent to the in vitro chemotaxis IC90 but only at much higher concentrations. To extend the results from our recruitment model, we tested one of the inhibitors in an allergenic model of airway inflammation, generated by adoptive transfer of OVA-sensitive murine T helper 2 cells and aerosolized OVA challenge of recipient mice, and found that it inhibited EPhi recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge.
Subject(s)
Cell Migration Inhibition , Disease Models, Animal , Eosinophils/metabolism , Lung/metabolism , Receptors, Chemokine/antagonists & inhibitors , Respiratory Hypersensitivity/metabolism , Animals , CHO Cells , Cricetinae , Eosinophils/drug effects , Eosinophils/immunology , Female , Humans , Inflammation/immunology , Inflammation/metabolism , Lung/immunology , Lung/pathology , Mice , Mice, Inbred BALB C , Mice, Knockout , Receptors, CCR3 , Receptors, Chemokine/immunology , Receptors, Chemokine/metabolism , Respiratory Hypersensitivity/immunologyABSTRACT
BACKGROUND: Repeated exposure to psychostimulants results in a progressive and long-lasting facilitation of the locomotor response that is thought to have implications for addiction. Psychostimulants and other drugs of abuse activate in specific brain areas extracellular signal-regulated kinase (ERK), an essential component of a signaling pathway involved in synaptic plasticity and long-term effects of drugs of abuse. Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain-penetrating selective inhibitor of MAP-kinase/ERK kinase (MEK), the enzyme that selectively activates ERK. RESULTS: A dose of SL327 (30 mg/kg) that reduced the number of activated ERK-positive neurons by 62 to 89% in various brain areas, had virtually no effect on the spontaneous locomotor activity or the acute hyperlocomotion induced by cocaine or D-amphetamine. Pre-treatment with SL327 (30 mg/kg) prior to each drug administration prevented the locomotor sensitization induced by repeated injections of D-amphetamine or cocaine. The SL327 pre-treatment abolished also conditioned locomotor response of mice placed in the context previously paired with cocaine or D-amphetamine. In contrast, SL327 did not alter the expression of sensitized response to D-amphetamine or cocaine. CONCLUSION: Altogether these results show that ERK has a minor contribution to the acute locomotor effects of psychostimulants or to the expression of sensitized responses, whereas it is crucial for the acquisition of locomotor sensitization and psychostimulant-conditioned locomotor response. This study supports the important role of the ERK pathway in long-lasting behavioral alterations induced by drugs of abuse.
Subject(s)
Brain/enzymology , Cocaine/pharmacology , Dextroamphetamine/pharmacology , Extracellular Signal-Regulated MAP Kinases/physiology , Motor Activity/drug effects , Psychotropic Drugs/pharmacology , Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/pharmacology , Animals , Behavior, Animal/drug effects , Brain/drug effects , Conditioning, Psychological/drug effects , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred C57BL , Phosphorylation/drug effectsABSTRACT
A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , ADAM17 Protein , Animals , Cell Line , Cyclization , Humans , Mice , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.
Subject(s)
Piperidines/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Urea/chemical synthesis , Calcium Signaling/drug effects , Chemokine CCL11 , Chemokines, CC/pharmacology , Drug Interactions , Eosinophils/drug effects , Humans , Inhibitory Concentration 50 , Piperidines/pharmacology , Protein Binding , Receptors, CCR3 , Structure-Activity Relationship , Urea/pharmacologyABSTRACT
Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.
Subject(s)
Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , Tumor Necrosis Factor-alpha/metabolism , ADAM Proteins , ADAM17 Protein , Animals , Caco-2 Cells , Humans , Metalloendopeptidases/metabolism , Mice , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Sulfones/pharmacologyABSTRACT
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 13 , Mice , Models, Molecular , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.
Subject(s)
Butadienes/chemical synthesis , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Nitriles/chemical synthesis , Animals , COS Cells , Chlorocebus aethiops , Mitogen-Activated Protein Kinase Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Succinates/chemical synthesis , ADAM Proteins , ADAM17 Protein , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Kinetics , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Succinates/chemistry , Succinates/pharmacologyABSTRACT
Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.