RESUMEN
Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 µg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6h and bioavailability of 23%.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Compuestos de Bifenilo/farmacología , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Procolágeno N-Endopeptidasa/metabolismo , Inhibidores de Proteasas/farmacología , Sulfonamidas/farmacología , Proteína ADAMTS4 , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Diseño de Fármacos , Humanos , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Modelos Moleculares , Osteoartritis/tratamiento farmacológico , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Proteoglicanos/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Dopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. Although there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here, we demonstrate that tyrosine-hydroxylase-2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal-fluid-contacting DA nuclei surrounding the 3rd ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.
Asunto(s)
Tronco Encefálico/fisiología , Neuronas Dopaminérgicas/metabolismo , Área Preóptica/fisiología , Natación/fisiología , Animales , Tronco Encefálico/citología , Potenciales Evocados Motores/fisiología , Genes Reporteros/genética , Proteínas Fluorescentes Verdes/genética , Microscopía Intravital/métodos , Masculino , Microscopía de Fluorescencia por Excitación Multifotónica , Modelos Animales , Red Nerviosa/fisiología , Optogenética , Área Preóptica/citología , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Grabación en Video , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The prevention of aggrecan (a key component of cartilage) cleavage via the inhibition of aggrecanase-1 may provide a unique opportunity to stop the progression of cartilage degradation in osteoarthritis. The evaluation of a series of biphenylsulfonamides resulted in the identification of the ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides analogs (19-21 and 24) with improved Agg-1 inhibition and MMP-2, MMP-13 activity.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Química Farmacéutica/métodos , Osteoartritis/tratamiento farmacológico , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Procolágeno N-Endopeptidasa/metabolismo , Sulfonamidas/síntesis química , Proteína ADAMTS4 , Cartílago/efectos de los fármacos , Cartílago/metabolismo , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Modelos Químicos , Conformación Molecular , Proteoglicanos/química , Sulfonamidas/farmacologíaRESUMEN
Aggrecanases are now believed to be the principal proteinases responsible for aggrecan degradation in osteoarthritis. Given their potential as a drug target, we solved crystal structures of the two most active human aggrecanase isoforms, ADAMTS4 and ADAMTS5, each in complex with bound inhibitor and one wherein the enzyme is in apo form. These structures show that the unliganded and inhibitor-bound enzymes exhibit two essentially different catalytic-site configurations: an autoinhibited, nonbinding, closed form and an open, binding form. On this basis, we propose that mature aggrecanases exist as an ensemble of at least two isomers, only one of which is proteolytically active.
Asunto(s)
Proteínas ADAM/química , Procolágeno N-Endopeptidasa/química , Proteína ADAMTS4 , Proteína ADAMTS5 , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Conformación ProteicaRESUMEN
N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-microM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/química , Acetamidas/síntesis química , Acetamidas/farmacología , Proteínas ADAM/metabolismo , Proteína ADAMTS4 , Proteína ADAMTS5 , Animales , Química Farmacéutica/métodos , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/efectos de los fármacos , Modelos Químicos , Osteoartritis/tratamiento farmacológico , Procolágeno N-Endopeptidasa/metabolismo , RatasRESUMEN
5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP12, and MMP13. This series of compounds represents progress toward a selective ADAMTS-5 inhibitor as a disease modifying osteoarthritis drug.
Asunto(s)
Endopeptidasas/metabolismo , Indoles/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Tiadiazoles/química , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Compuestos de Espiro/síntesis química , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacologíaRESUMEN
5-Benzylidene-2-thioxo-thiazolidin-4-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. The identified compounds show micromolar ADAMTS-5 potency and demonstrate SAR trends for both the aryl group and thioxothiazolidinone zinc chelator. This series of compounds represents steps toward a metalloprotease inhibitor as a disease-modifying osteoarthritis drug.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Tiazolidinedionas/síntesis química , Tiazolidinedionas/farmacología , Proteína ADAMTS5 , Quelantes , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Metaloproteasas/antagonistas & inhibidores , Osteoartritis/tratamiento farmacológico , Relación Estructura-Actividad , ZincRESUMEN
A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Tiazolidinedionas/síntesis química , Proteína ADAMTS4 , Proteína ADAMTS5 , Agrecanos/efectos de los fármacos , Agrecanos/metabolismo , Cartílago , Humanos , Concentración 50 Inhibidora , Osteoporosis/tratamiento farmacológico , Procolágeno N-Endopeptidasa , Relación Estructura-Actividad , Tiazolidinedionas/farmacologíaRESUMEN
Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%.