RESUMEN
A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Acetileno/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Proteína ADAM17 , Administración Oral , Alquinos/química , Animales , Artritis/tratamiento farmacológico , Células CACO-2 , Colágeno/toxicidad , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Perros , Haplorrinos , Humanos , Ácidos Hidroxámicos/química , Lipopolisacáridos/farmacología , Metaloproteinasa 13 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Ratones , Estructura Molecular , Morfolinas/química , Propanoles/química , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Ácidos Hidroxámicos/síntesis química , Sulfonamidas/síntesis química , Proteína ADAM17 , Animales , Disponibilidad Biológica , Inhibidores de Caspasas , Línea Celular , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Perros , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Monocitos , Ratas , Especificidad de la Especie , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/efectos de los fármacosRESUMEN
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
Asunto(s)
Acetileno/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , ortoaminobenzoatos/química , Proteínas ADAM , Proteína ADAM17 , Cristalografía por Rayos X , Ácidos Hidroxámicos/química , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/química , ortoaminobenzoatos/farmacologíaRESUMEN
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Metaloendopeptidasas/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Animales , Artritis/tratamiento farmacológico , Artritis/patología , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cartílago/efectos de los fármacos , Cartílago/patología , Bovinos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.
Asunto(s)
Acetileno/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacología , Proteínas ADAM , Proteína ADAM17 , Relación Estructura-ActividadRESUMEN
Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.
Asunto(s)
Aminas/química , Inhibidores Enzimáticos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , ortoaminobenzoatos/farmacología , Proteínas ADAM , Proteína ADAM17 , Animales , Sitios de Unión , Colagenasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/química , Interleucina-1 , Interleucina-1beta , Espectroscopía de Resonancia Magnética , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloendopeptidasas , Ratones , Modelos Moleculares , Osteoartritis/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/químicaRESUMEN
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , ortoaminobenzoatos/farmacología , Proteínas ADAM , Proteína ADAM17 , Colagenasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/metabolismo , Relación Estructura-Actividad , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/químicaRESUMEN
Heteroaryl and cycloalkyl sulfonamide-hydroxamic acid MMP inhibitors were investigated. Of these, the pyridyl analogue 2 is the most potent and selective inhibitor of MMP-9 and MMP-13 in vitro.
Asunto(s)
Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , ortoaminobenzoatos/farmacología , Animales , Técnicas Químicas Combinatorias , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Metaloproteinasa 13 de la Matriz , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/químicaRESUMEN
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, and MMP-13 was prepared and evaluated both in vitro and in vivo. The most potent compound, 6e, has in vivo activity in a rat sponge-wrapped cartilage model.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , ortoaminobenzoatos/farmacología , Animales , Técnicas Químicas Combinatorias , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Concentración 50 Inhibidora , Metaloproteinasa 13 de la Matriz , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/químicaRESUMEN
Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Animales , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/patología , Arteriosclerosis/fisiopatología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Tejido Conectivo/enzimología , Tejido Conectivo/patología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Matriz Extracelular/enzimología , Humanos , Metástasis de la Neoplasia , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Osteoartritis/fisiopatología , Enfermedades Periodontales/tratamiento farmacológico , Enfermedades Periodontales/patología , Enfermedades Periodontales/fisiopatologíaRESUMEN
The solution structure of the catalytic fragment of human fibroblast collagenase (MMP-1) complexed with a sulfonamide derivative of a hydroxamic acid compound (CGS-27023A) has been determined using two-dimensional and three-dimensional heteronuclear NMR spectroscopy. The solution structure of the complex was calculated by means of hybrid distance geometry-simulated annealing using a combination of experimental NMR restraints obtained from the previous refinement of the inhibitor-free MMP-1 (1) and recent restraints for the MMP-1:CGS-27023A complex. The hydroxamic acid moiety of CGS-27023A was found to chelate to the "right" of the catalytic zinc where the p-methoxyphenyl sits in the S1' active-site pocket, the isopropyl group is in contact with H83 and N80, and the pyridine ring is solvent exposed. The sulfonyl oxygens are in hydrogen-bonding distance to the backbone NHs of L81 and A82. This is similar to the conformation determined by NMR of the inhibitor bound to stromelysin (2, 3). A total of 48 distance restraints were observed between MMP-1 and CGS-27023A from 3D 13C-edited/12C-filtered NOESY and 3D 15N-edited NOESY experiments. An additional 18 intramolecular restraints were observed for CGS-27023A from a 2D 12C-filtered NOESY experiment. A minimal set of NMR experiments in combination with the free MMP-1 assignments were used to assign the MMP-1 (1)H, 13C, and 15N resonances in the MMP-1:CGS-27023A complex. The assignments of CGS-27023A in the complex were obtained from 2D 12C-filtered NOESY and 2D 12C-filtered TOCSY experiments.
Asunto(s)
Colagenasas/química , Fibroblastos/enzimología , Ácidos Hidroxámicos/química , Fragmentos de Péptidos/química , Inhibidores de Proteasas/química , Pirazinas , Sulfonamidas/química , Catálisis , Simulación por Computador , Cristalografía por Rayos X , Humanos , Sustancias Macromoleculares , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 3 de la Matriz/química , Metaloproteinasa 8 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/antagonistas & inhibidores , Conformación Proteica , SolucionesRESUMEN
A novel series of matrix metalloproteinase (MMP) inhibitors is described. Incorporation of a terminal alpha-mercaptoketone or alpha-mercaptoalcohol in the zinc binding domain of a series of inhibitors led to compounds exhibiting low nanomolar activity against collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).
Asunto(s)
Alcoholes/química , Cetonas/química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Compuestos de Sulfhidrilo/química , Alcoholes/síntesis química , Alcoholes/farmacología , Sitios de Unión , Diseño de Fármacos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Cetonas/síntesis química , Cetonas/farmacología , Cinética , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 9 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/farmacología , Zinc/metabolismoRESUMEN
A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).
Asunto(s)
Alcoholes/síntesis química , Cetonas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Succinatos/síntesis química , Compuestos de Sulfhidrilo/síntesis química , Alcoholes/química , Alcoholes/farmacología , Diseño de Fármacos , Indicadores y Reactivos , Cetonas/química , Cetonas/farmacología , Cinética , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 9 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Estructura Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Succinatos/química , Succinatos/farmacología , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
A novel series of diazepine-based hydroxamic acid inhibitors of MMP-1, MMP-9, and MMP-13 were prepared and evaluated both in vitro and in vivo.
Asunto(s)
Azepinas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Compuestos Orgánicos , Pirazinas , Animales , Antineoplásicos/farmacología , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 9 de la Matriz , Ratones , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.
Asunto(s)
Acetilcisteína/análogos & derivados , Cartílago Articular/enzimología , Cisteína/análogos & derivados , Interleucina-1/farmacología , Inhibidores de Proteasas/farmacología , Pirazoles/farmacología , Animales , Benzotiazoles , Cartílago Articular/patología , Cisteína/farmacología , Endopeptidasas/análisis , Endopeptidasas/biosíntesis , Inducción Enzimática/efectos de los fármacos , Miembro Posterior , Técnicas In Vitro , Masculino , Colagenasa Microbiana/análisis , ConejosRESUMEN
The synthesis and in vitro antibacterial profile of a series of (Z)-(2-amino-4-thiazolyl)-[(2,3-dialkoxypropoxy)imino]acetyl derivatives of 7-aminocephalosporanic acid and 3-aminomonobactamic acid are reported.
Asunto(s)
Antibacterianos/síntesis química , Tiazoles/síntesis química , beta-Lactamas/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Cefalosporinas/síntesis química , Relación Estructura-Actividad , Tiazoles/farmacología , beta-Lactamas/farmacologíaRESUMEN
The synthesis of C-3' isothiazolyl and related cephalosporins is presented. The compounds exhibit activity against a variety of Gram-positive and Gram-negative organisms.