RESUMEN
Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson's disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC50 = 0.37 µM), metal chelation ability, and BBB permeability. Furthermore, results from in vivo biological activity evaluations indicate that C12 can improve dopamine levels and ameliorate MPTP-induced PD symptoms in mice. Preliminary in vivo and in vitro study results highlight the potential of compound C12 in PD treatment.
Asunto(s)
Dopamina , Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Enfermedad de Parkinson , Animales , Ratones , Dopamina/metabolismo , Relación Estructura-Actividad , Monoaminooxidasa/metabolismo , Estructura Molecular , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/síntesis química , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Catecol O-Metiltransferasa/metabolismo , Ratones Endogámicos C57BL , Masculino , Inhibidores de Catecol O-Metiltransferasa/farmacología , Inhibidores de Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Humanos , Relación Dosis-Respuesta a Droga , Antiparkinsonianos/farmacología , Antiparkinsonianos/química , Antiparkinsonianos/síntesis química , Antiparkinsonianos/uso terapéuticoRESUMEN
The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson's disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 µM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 µM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecoles/farmacología , Indanos/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Nitrocompuestos/farmacología , Tetralonas/farmacología , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Catecoles/química , Relación Dosis-Respuesta a Droga , Humanos , Indanos/síntesis química , Indanos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Nitrocompuestos/química , Relación Estructura-Actividad , Tetralonas/síntesis química , Tetralonas/químicaRESUMEN
The most effective treatment of Parkinson's disease is restoring central dopamine levels with levodopa, the metabolic precursor of dopamine. However, due to extensive peripheral metabolism by aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT), only a fraction of the levodopa dose reaches the brain unchanged. Thus, by preventing levodopa metabolism and increasing the availability of levodopa for uptake into the brain, the inhibition of COMT would be beneficial in Parkinson's disease. Although nitrocatechol COMT inhibitors have been used in the treatment of Parkinson's disease, efforts have been made to discover non-nitrocatechol inhibitors. In the present study, the 3-hydroxypyridin-4-one scaffold was selected for the design and synthesis of non-nitrocatechol COMT inhibitors since the COMT inhibitory potential of this class has been illustrated. Using COMT obtained from porcine liver, it was shown that a synthetic series of ten 3-hydroxypyridin-4-ones are in vitro inhibitors with IC50 values ranging from 4.55 to 19.8 µM. Although these compounds are not highly potent inhibitors, they may act as leads for the development of non-nitrocatechol COMT inhibitors. Such compounds would be appropriate for the treatment of Parkinson's disease. 3-Hydroxypyridin-4-ones have been synthesised and evaluated as non-nitrocatechol COMT inhibitors. In vitro, the IC50 values ranged from 4.55 to 19.8 µM.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa , Piridinas , Animales , Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Diseño de Fármacos , Hígado/enzimología , Modelos Moleculares , Piridinas/síntesis química , Piridinas/química , PorcinosRESUMEN
Catechol O-methyltransferase (COMT) is known as an important drug-target protein in the field of Parkinson's disease. All clinically approved COMT inhibitors bring a 5-substituted-3-nitrocatechol ring as a pharmacophore, and they bind to COMT with S-adenosylmethionine (SAM) and an Mg2+ ion to form a quaternary complex (COMT/SAM/Mg2+/inhibitor). However, structural information about such quaternary complexes is only available for a few inhibitors. Here, a new crystal structure of COMT complexed with nitecapone (5), SAM and Mg2+ is revealed. Comparison of the structures of these complexes indicates that conformation of the catechol binding pocket is almost constant regardless of structure of the inhibitors. The only restriction of the side chain of inhibitors (i.e., the substituent at the 5-position of 3-nitrocatechol) seems to be that it does not make steric repulsion with COMT. However, recent crystallographic and biochemical studies suggest that COMT is a flexible protein, and its conformational flexibility seems crucial for its catalytic process. Based on this information, implications of these quaternary inhibitor complexes were investigated. Met 40 in the α2α3-loop makes atomic contacts with SAM or S-adenosylhomocysteine and the 3-position of the catechol inhibitor. This interaction seems to play a critical role in the affinity of the inhibitor and to stabilize the COMT/SAM/Mg2+/nitrocatechol inhibitor complex by fixing the flexible α2α3-loop.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Catecoles/farmacología , Pentanonas/farmacología , Catecol O-Metiltransferasa/aislamiento & purificación , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Catecoles/síntesis química , Catecoles/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Pentanonas/síntesis química , Pentanonas/química , Relación Estructura-ActividadRESUMEN
Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol-O-methyltransferase (COMT). Based on this, nitrocatechol derivatives of chalcone have been proposed to represent dual-target-directed compounds that may inhibit both MAO-B and COMT. Both these enzymes play key roles in the metabolism of dopamine and levodopa, and inhibitors are thus relevant to the treatment of Parkinson's disease. The present study expands on the discovery of dual MAO-B/COMT inhibitors by synthesising additional nitrocatechol derivatives of chalcones which include heterocyclic derivatives, and converting them to the corresponding pyrazoline derivatives. The newly synthesised chalcone and pyrazoline compounds were evaluated as inhibitors of human MAO and rat COMT, and the inhibition potencies were expressed as IC50 values. A pyrazoline derivative, compound 8b, was the most potent COMT inhibitor with an IC50 value of 0.048 µM. This is more potent than the reference COMT inhibitor, entacapone, which has an IC50 value of 0.23 µM. The results indicated that the pyrazoline derivatives (IC50 = 0.048-0.21 µM) are more potent COMT inhibitors than the chalcones (IC50 = 0.14-0.29 µM). Unfortunately, the chalcone and pyrazoline derivatives were weak MAO inhibitors with IC50 values > 41.4 µM. This study concludes that the nitrocatechol derivatives investigated here are promising COMT inhibitors, while not being suitable as MAO inhibitors. Using molecular docking, potential binding modes and interactions of selected inhibitors with COMT are proposed.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Animales , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Catecoles/síntesis química , Catecoles/química , Catecoles/farmacología , Chalconas/síntesis química , Chalconas/química , Chalconas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Nitrocompuestos/síntesis química , Nitrocompuestos/química , Nitrocompuestos/farmacología , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Diseño de Fármacos , S-Adenosilmetionina/farmacología , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Estructura Molecular , S-Adenosilmetionina/síntesis química , S-Adenosilmetionina/química , Relación Estructura-ActividadRESUMEN
Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 µM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.
Asunto(s)
Benzofenonas/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Catecoles/farmacología , Hepatocitos/efectos de los fármacos , Nitrilos/farmacología , Nitrofenoles/farmacología , Animales , Benzofenonas/síntesis química , Benzofenonas/química , Barrera Hematoencefálica/metabolismo , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Catecoles/síntesis química , Catecoles/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hepatocitos/metabolismo , Masculino , Modelos Moleculares , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/química , Nitrofenoles/síntesis química , Nitrofenoles/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , TolcaponaRESUMEN
A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Compuestos Heterocíclicos/farmacología , Piridonas/farmacología , Animales , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Modelos Moleculares , Estructura Molecular , Piridonas/síntesis química , Piridonas/química , Ratas , Relación Estructura-ActividadRESUMEN
Structurally related inhibitors of a shared therapeutic target may differ regarding potential toxicity issues that are caused by different off-target bindings. We devised a differential competition capture compound mass spectrometry (dCCMS) strategy to effectively differentiate off-target profiles. Tolcapone and entacapone are potent inhibitors of catechol-O-methyl transferase (COMT) for the treatment of Parkinson's disease. Tolcapone is also known for its hepatotoxic side effects even though it is therapeutically more potent than entacapone. Here, we identified 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) as a possible toxicity-causing off-target of tolcapone, and this protein is not bound by the less toxic COMT inhibitor entacapone. Moreover, two novel compounds from a focused library synthesized in-house, N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide and 5-(3,4-dihydroxy-5-nitrobenzylidene)-3-ethylthiazolidine-2,4-dione, were utilized to gain insight into the structure-activity relationships in binding to COMT and the novel off-target HIBCH. These compounds, especially N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide, could serve as starting point for the development of improved and more specific COMT inhibitors.