RESUMEN
A novel cyclohexenyl series of CCR2 antagonists has been discovered. This series of small, rigid compounds exhibits submicromolar binding affinity for CCR2. Modification of the substituents on the cyclohexene ring led to the identification of potent CCR2 antagonists. Progress from initial lead 5 (IC50=700nM) to (-)-38 (IC50=9.0nM) is discussed.
Asunto(s)
Ciclohexenos/química , Ciclohexenos/farmacología , Receptores CCR2/antagonistas & inhibidores , Ciclohexenos/síntesis química , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Receptores CCR2/metabolismo , Relación Estructura-ActividadRESUMEN
The title amidine compound, C14H20N2, prepared by a one-pot reaction, is asymmetric as only one N atom has an alkyl substituent. The terminal cyclo-hexyl group connected to the amino N atom is located on the other side of the N-C-N skeleton to the 4-methylbenzene ring and has a chair conformation. The dihedral angle between the phenyl ring and the NCN plane is 47.87â (12)°. In the crystal, mol-ecules are linked via N-Hâ¯N hydrogen bonds, forming chains propagating along the a-axis direction.
RESUMEN
Exosomes play important roles in many physiological and pathological processes. However, the exosome-cell interaction mode and the intracellular trafficking pathway of exosomes in their recipient cells remain unclear. Here, we report that exosomes derived from K562 or MT4 cells are internalized more efficiently by phagocytes than by non-phagocytic cells. Most exosomes were observed attached to the plasma membrane of non-phagocytic cells, while in phagocytic cells these exosomes were found to enter via phagocytosis. Specifically, they moved to phagosomes together with phagocytic polystyrene carboxylate-modified latex beads (biospheres) and were further sorted into phagolysosomes. Moreover, exosome internalization was dependent on the actin cytoskeleton and phosphatidylinositol 3-kinase, and could be inhibited by the knockdown of dynamin2 or overexpression of a dominant-negative form of dynamin2. Further, antibody pretreatment assays demonstrated that tim4 but not tim1 was involved in exosomes uptake. We also found that exosomes did not enter the internalization pathway involving caveolae, macropinocytosis and clathrin-coated vesicles. Our observation that the cellular uptake of exosomes occurs through phagocytosis has important implications for exosome-cell interactions and the exosome intracellular trafficking pathway.
Asunto(s)
Exosomas/metabolismo , Transporte Biológico , Caveolas/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Células/metabolismo , Vesículas Cubiertas por Clatrina/metabolismo , Citoesqueleto/metabolismo , Humanos , Fagocitosis , Fosfatidilinositol 3-Quinasas/metabolismo , Transporte de ProteínasRESUMEN
beta-Amyloid peptide (Abeta42) is the core protein of amyloid plaque in Alzheimer disease. The intracellular accumulation of Abeta42 in the endosomal/lysosomal system has been under investigation for many years, but the direct link between Abeta42 accumulation and dysfunction of the endosomal/lysosomal system is still largely unknown. Here, we found that both in vitro and in vivo, a major portion of Abeta42 was tightly inserted into and a small portion peripherally associated with the lysosomal membrane, whereas its soluble portion was minimal. We also found that the Abeta42 molecules inserted into the membrane tended to form multiple oligomeric aggregates, whereas Abeta40 peptides formed only dimers. Neutralizing lysosomal pH in differentiated PC12 cells decreased the lysosomal membrane insertion of Abeta42 and moderated Abeta42-induced lysosomal labilization and cytotoxicity. Our findings, thus, suggest that the membrane-inserted portion of Abeta42 accumulated in lysosomes may destabilize the lysosomal membrane and induce neurotoxicity.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Membranas Intracelulares/metabolismo , Lisosomas/metabolismo , Fragmentos de Péptidos/metabolismo , Factores de Edad , Péptidos beta-Amiloides/química , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Western Blotting , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Membranas Intracelulares/efectos de los fármacos , Membrana Dobles de Lípidos/metabolismo , Ratones , Ratones Transgénicos , Células PC12 , Fragmentos de Péptidos/química , Multimerización de Proteína , Transporte de Proteínas/efectos de los fármacos , Ratas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Benzofuranos/química , Imidazoles/química , Indoles/química , Inhibidores de Proteasas/farmacología , Pirazoles/química , Piridinas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Ácidos Hidroxámicos/química , Lipopolisacáridos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Proteínas ADAM/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administración Oral , Animales , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacología , Sitios de Unión , Disponibilidad Biológica , Perros , Ácidos Hidroxámicos/farmacocinética , Modelos Moleculares , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , PorcinosRESUMEN
Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Proteína ADAM17 , Administración Oral , Animales , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/síntesis química , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacocinética , Ratas , EstereoisomerismoRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Alcanos/química , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Compuestos de Espiro/química , Proteína ADAM17 , Administración Oral , Alcanos/síntesis química , Alcanos/farmacocinética , Alcanos/farmacología , Animales , Disponibilidad Biológica , Células CACO-2 , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacocinética , Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacologíaRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Benzamidas/química , Benzamidas/farmacología , Proteína ADAM17 , Animales , Área Bajo la Curva , Benzamidas/sangre , Benzamidas/farmacocinética , Disponibilidad Biológica , Perros , Semivida , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
PURPOSE: The efficacy of three matrix metalloproteinase (MMP) inhibitors with various selectivities (Ro-31-9790, AG3340, and DPC-A37668) was investigated in a rat model of retinopathy of prematurity, to examine the roles of MMP-2 and -9 in retinal neovascularization. The susceptibilities of MMP-2(-/-) and -9(-/-) mice to preretinal neovascularization were investigated in a mouse model of oxygen-induced retinopathy. METHODS: Sprague-Dawley newborn rats were exposed to alternating episodes of 50% and 10% oxygen (variable oxygen exposure) to induce retinal neovascularization. Three MMP inhibitors with various selectivity profiles were administered to variable oxygen-exposed rats via local or systemic routes. Antineovascular efficacy was determined in drug-treated versus vehicle-treated rat pups by computerized imaging of adenosine diphosphatase (ADPase)-stained retinal flatmounts. Wild-type C57BL/6J and isogenic MMP-2(-/-) and -9(-/-) mice were exposed to 75% oxygen followed by normoxia. The mice were killed immediately before or after the normoxic exposure, and eyes were either harvested for retinal dissection and flatmounting or were paraffin embedded and sectioned. Retinal vascular area and retinal neovascularization were assessed by adenosine diphosphatase staining of retinal flatmounts and by counting preretinal nuclei of hematoxylin and eosin-stained retinal sections, respectively. RESULTS: Ro-31-9790, AG3340, and DPC-A37668 had no effect on normal development of the rat retinal vasculature, regardless of dose or route of administration. Intravitreal injection of Ro-31-9790 (broad-spectrum) immediately after variable-oxygen exposure and 2 days after exposure resulted in 78% and 82% inhibition of retinal neovascularization, respectively. AG3340 (MMP-2- and -9-selective inhibitor) and DPC-A37668 (MMP-2-selective inhibitor) resulted in 65% and 52% inhibition, respectively, when administered by intravitreal injection immediately after variable-oxygen exposure. Intraperitoneal injection of 5, 15, and 50 mg/mL AG3340 or DPC-A37668 for 6 days after variable oxygen exposure resulted in 22% to 39% and 0% to 31% inhibition of neovascularization, respectively. AG3340 and DPC-A37668 administered by oral gavage at doses of 3, 10, or 30 mg/mL provided up to 42% and 86% inhibition of neovascularization, respectively. The average vascular areas of retinas from MMP-2(-/-) or -9(-/-) mice at postnatal day 12 were not significantly different from the wild-type control. There was a 75% (P < 0.001) and 44% (P < 0.01) reduction in preretinal neovascularization in oxygen-exposed MMP-2(-/-) and -9(-/-) mice at postnatal day 19, respectively, compared with wild-type control mice. CONCLUSIONS: The results of this study suggest that MMP-2 plays a predominant role in retinal angiogenesis in both the mouse and rat models of oxygen-induced retinopathy. Furthermore, MMP-2 inhibition may be a viable therapeutic approach for ocular diseases characterized by retinal neovascularization.
Asunto(s)
Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Silenciador del Gen/fisiología , Metaloproteinasa 2 de la Matriz/fisiología , Metaloproteinasa 9 de la Matriz/fisiología , Neovascularización Retiniana/enzimología , Retinopatía de la Prematuridad/enzimología , Animales , Animales Recién Nacidos , Apirasa/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Recién Nacido , Inyecciones , Inhibidores de la Metaloproteinasa de la Matriz , Ratones , Ratones Endogámicos C57BL , Compuestos Orgánicos/farmacología , Oxígeno/toxicidad , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Retina/enzimología , Neovascularización Retiniana/tratamiento farmacológico , Neovascularización Retiniana/patología , Retinopatía de la Prematuridad/tratamiento farmacológico , Retinopatía de la Prematuridad/patología , Cuerpo VítreoRESUMEN
The asymmetric unit of the title compound, C15H16N2·C4H8O, contains two amidine mol-ecules (A and B) with slightly different conformations and two tetra-hydro-furan (THF) solvent mol-ecules. In the amidine mol-ecules, the di-methyl-phenyl ring and the NH2 group lie to the same side of the N=C bond and the dihedral angles between the aromatic rings are 54.25â (7) (mol-ecule A) and 58.88â (6) ° (mol-ecule B). In the crystal, N-Hâ¯N hydrogen bonds link the amidine mol-ecules into [100] C(4) chains of alternating A and B mol-ecules. Both amidine mol-ecules form an N-Hâ¯O hydrogen bond to an adjacent THF solvent mol-ecule.
RESUMEN
ADAM-TS5 (aggrecanase 2), one of two cartilage aggrecanases is a member of the ADAM protein family. Like ADAM-TS4 (aggrecanase 1) the enzyme cleaves cartilage aggrecan at the Glu(373)-Ala(374) bond, a marker of aggrecanase activity. In this study we have characterized the substrate specificity of ADAM-TS5 and compared it with that of ADAM-TS4. The recombinant human ADAM-TS5, like ADAM-TS4 cleaves aggrecan at Glu(1480)-Gly(1481), Glu(1667)-Gly(1668), Glu(1771)-Ala(1772) and Glu(1871)-Leu(1872) bonds more readily than at the Glu(373)-Ala(374) bond. In addition, ADAM-TS5 exhibited an additional site of cleavage in the region spanning residues Gly(1481) and Glu(1667), representing a unique cleavage of ADAM-TS5. ADAM-TS5 cleaved aggrecan approximately 2-fold slower than ADAM-TS4. Neither ADAM-TS5 nor ADAM-TS4 was able to cleave the extracellular matrix proteins fibronectin, thrombospondin, type I collagen, type II collagen, gelatin or general protein substrates such as casein and transferrin. Finally, the zymogen of stromelysin (MMP-3) was not activated by either ADAM-TS4 or ADAM-TS5.
Asunto(s)
Metaloendopeptidasas/metabolismo , Proteínas ADAM , Proteína ADAMTS4 , Proteína ADAMTS5 , Agrecanos , Animales , Línea Celular , Drosophila/citología , Proteínas de la Matriz Extracelular/efectos de los fármacos , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Lectinas Tipo C , Metaloendopeptidasas/farmacología , Procolágeno N-Endopeptidasa , Proteoglicanos/química , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Especificidad por Sustrato , Factores de TiempoRESUMEN
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.
Asunto(s)
Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Sulfonamidas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Metaloproteinasa 13 de la Matriz , Ratones , Modelos Moleculares , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
Asunto(s)
Ácidos Hidroxámicos/síntesis química , Lactamas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Proteínas ADAM , Proteína ADAM17 , Administración Oral , Animales , Disponibilidad Biológica , Perros , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Lactamas/química , Lactamas/farmacología , Metaloproteinasa 3 de la Matriz/química , Modelos Moleculares , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , PorcinosRESUMEN
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
Asunto(s)
Benzodiazepinonas/síntesis química , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Tiazepinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Animales , Benzodiazepinonas/química , Benzodiazepinonas/farmacología , Proteínas Sanguíneas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz , Modelos Moleculares , Unión Proteica , Relación Estructura-Actividad , Porcinos , Tiazepinas/química , Tiazepinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.
Asunto(s)
Quimiotaxis/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Monocitos/efectos de los fármacos , Piperidinas/farmacología , Receptores CCR/antagonistas & inhibidores , Animales , Calcio/metabolismo , Células Cultivadas , Humanos , Ratones , Monocitos/citología , Técnicas de Placa-Clamp , Piperidinas/síntesis química , Piperidinas/farmacocinética , Unión Proteica , Conejos , Ratas , Receptores CCR/metabolismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
We have discovered selective and potent inhibitors of TACE that replace the common hydroxamate zinc binding group with a hydantoin, triazolone, and imidazolone heterocycle. These novel heterocyclic inhibitors of a zinc metalloprotease were designed using a pharmacophore model that we previously described while developing hydantoin and pyrimidinetrione (barbiturate) inhibitors of TACE. The potency and binding orientation of these inhibitors is discussed and they are modeled into the X-ray crystal structure of TACE and compared to hydroxamate and earlier hydantoin TACE inhibitors which share the same 4-[(2-methyl-4-quinolinyl)methoxy]benzoyl P1' group.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hidantoínas/farmacología , Imidazoles/farmacología , Triazoles/farmacología , Proteína ADAM17 , Inhibidores Enzimáticos/química , Hidantoínas/química , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Imidazoles/química , Modelos Moleculares , Estructura Molecular , Triazoles/químicaRESUMEN
A novel series of TNF-alpha converting enzyme (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds use a triazolethione moiety as the zinc binding ligand and exhibit IC50 values from 1.5 to 100 nM in a porcine TACE assay. They also have excellent selectivities over other MMPs.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Proteína ADAM17 , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Compuestos Heterocíclicos/química , Estructura Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Hidantoínas/síntesis química , Hidantoínas/farmacología , Proteína ADAM17 , Animales , Diseño de Fármacos , Concentración 50 Inhibidora , Relación Estructura-Actividad , Especificidad por Sustrato , PorcinosRESUMEN
Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.