RESUMO
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.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Nitrogênio/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Enxofre/química , Tiazóis/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
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.
Assuntos
Nefropatias/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Animais , Butadienos/administração & dosagem , Butadienos/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Obstrução Ureteral/cirurgiaRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Alcanos/química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Compostos de Espiro/química , Proteína ADAM17 , Administração Oral , Alcanos/síntese química , Alcanos/farmacocinética , Alcanos/farmacologia , Animais , Disponibilidade Biológica , Células CACO-2 , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/metabolismo , Modelos Moleculares , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologiaRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzofuranos/química , Imidazóis/química , Indóis/química , Inibidores de Proteases/farmacologia , Pirazóis/química , Piridinas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Ácidos Hidroxâmicos/química , Lipopolissacarídeos/farmacologia , Inibidores de Metaloproteinases de Matriz , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzamidas/química , Benzamidas/farmacologia , Proteína ADAM17 , Animais , Área Sob a Curva , Benzamidas/sangue , Benzamidas/farmacocinética , Disponibilidade Biológica , Cães , Meia-Vida , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzotiazóis/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/enzimologia , Cristalografia por Raios X , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas ADAM/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Cães , Ácidos Hidroxâmicos/farmacocinética , Modelos Moleculares , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , SuínosRESUMO
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.
Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Glomerulonefrite/enzimologia , Animais , Células Cultivadas , Mesângio Glomerular/citologia , Mesângio Glomerular/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Endotoxemia/tratamento farmacológico , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Proteína ADAM17 , Adulto , Animais , Anti-Inflamatórios/sangue , Artrite Experimental/sangue , Artrite Experimental/patologia , Cães , Método Duplo-Cego , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Feminino , Humanos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pan troglodytes , Quinolinas/sangue , Ratos , Ratos Endogâmicos , Líquido Sinovial/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangueRESUMO
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.
Assuntos
Sondas Moleculares/fisiologia , Oxazepinas/farmacologia , Hormônio Paratireóideo/fisiologia , Fragmentos de Peptídeos/fisiologia , Receptor Tipo 1 de Hormônio Paratireóideo/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Ligação Competitiva , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Técnicas de Sonda Molecular , Dados de Sequência Molecular , Oxazepinas/agonistas , Hormônio Paratireóideo/agonistas , Hormônio Paratireóideo/metabolismo , Fragmentos de Peptídeos/agonistas , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Hormônio Paratireóideo/agonistas , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismoRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Química Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Ácidos Hidroxâmicos/química , Proteínas ADAM/sangue , Proteína ADAM17 , Animais , Cães , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Oxigênio/química , Ratos , Relação Estrutura-Atividade , SuínosRESUMO
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.
Assuntos
Inibição de Migração Celular , Modelos Animais de Doenças , Eosinófilos/metabolismo , Pulmão/metabolismo , Receptores de Quimiocinas/antagonistas & inibidores , Hipersensibilidade Respiratória/metabolismo , Animais , Células CHO , Cricetinae , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores CCR3 , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Hipersensibilidade Respiratória/imunologiaRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteína ADAM17 , Animais , Linhagem Celular , Ciclização , Humanos , Camundongos , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Encéfalo/enzimologia , Cocaína/farmacologia , Dextroanfetamina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Atividade Motora/efeitos dos fármacos , Psicotrópicos/farmacologia , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacosRESUMO
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.
Assuntos
Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Ureia/síntese química , Sinalização do Cálcio/efeitos dos fármacos , Quimiocina CCL11 , Quimiocinas CC/farmacologia , Interações Medicamentosas , Eosinófilos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Piperidinas/farmacologia , Ligação Proteica , Receptores CCR3 , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
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.
Assuntos
Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Proteínas ADAM , Proteína ADAM17 , Animais , Células CACO-2 , Humanos , Metaloendopeptidases/metabolismo , Camundongos , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologiaRESUMO
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.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 13 da Matriz , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
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.
Assuntos
Butadienos/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nitrilas/síntese química , Animais , Células COS , Chlorocebus aethiops , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Metaloendopeptidases/antagonistas & inibidores , Succinatos/síntese química , Proteínas ADAM , Proteína ADAM17 , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cinética , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Succinatos/química , Succinatos/farmacologiaRESUMO
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.