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1.
Bioorg Med Chem Lett ; 29(15): 1968-1973, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31133534

RESUMEN

Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer's Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.


Asunto(s)
Glicoproteínas/uso terapéutico , Pirrolidinas/metabolismo , Glicoproteínas/farmacología , Humanos , Relación Estructura-Actividad
2.
Am J Pathol ; 181(2): 616-25, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22688056

RESUMEN

Calpains are cysteine proteinases that selectively cleave proteins in response to calcium signals. Exacerbated activation of calpain has been implicated as a major component in the signaling cascade that leads to ß-amyloid (Aß) production and tau hyperphosphorylation in Alzheimer's disease (AD). In this study, we analyzed the potential therapeutic efficacy of inhibiting the activation of calpain by a novel calpain inhibitor in aged 3xTgAD mice with well-established cognitive impairment, plaques, and tangles. The administration of a novel inhibitor of calpain, A-705253, attenuated cognitive impairment and synaptic dysfunction in a dose-dependent manner in 3xTgAD mice. Inhibition of calpain lowered Aß(40) and Aß(42) levels in both detergent-soluble and detergent-insoluble fractions and also reduced the total number and size of thioflavin S-positive fibrillar Aß deposits. Mechanistically, these effects were, in part, explained by a down-regulation of ß-secretase 1 (BACE1) and an up-regulation of ATP-binding cassette transporter A1 (ABCA1) expression, which, in turn, contributed to reduced production and increased clearance of Aß, respectively. Moreover, A-705253 decreased the activation of cyclin-dependent kinase 5 (CDK5) and thereby diminished the hyperphosphorylation of tau. Finally, blockage of calpain activation reduced the astrocytic and microglial responses associated with AD-like pathological characteristics in aged 3xTgAD mice. Our data provide relevant functional and molecular insights into the beneficial therapeutic effects of inhibiting calpain activation for the management of AD.


Asunto(s)
Envejecimiento/patología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Benzamidas/farmacología , Benzamidas/uso terapéutico , Cognición/efectos de los fármacos , Glicoproteínas/uso terapéutico , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Envejecimiento/efectos de los fármacos , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/fisiopatología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/metabolismo , Activación Enzimática/efectos de los fármacos , Glicoproteínas/farmacología , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Sistema Nervioso/efectos de los fármacos , Sistema Nervioso/patología , Fosforilación/efectos de los fármacos , Proteínas tau/metabolismo
3.
Neurochem Int ; 53(3-4): 79-88, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18590784

RESUMEN

We have previously shown that beta-amyloid (Abeta) oligomers induced dynamin 1 and tau cleavage in cultured hippocampal neurons. As a result of this cleavage, dynamin 1 levels decreased and a toxic tau fragment was generated. Abeta-induced cleavage of these proteins was calpain-mediated and impacted both synaptic vesicle recycling and the integrity of neuronal processes [Kelly, B.L., Vassar, R., Ferreira, A., 2005. Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J. Biol. Chem. 280, 31746-31753; Park, S.Y., Ferreira, A., 2005. The generation of a 17kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J. Neurosci. 25, 5365-5375; Kelly, B.L., Ferreira, A., 2006. Beta-amyloid-induced dynamin 1 degradation is mediated by N-methyl-d-aspartate receptors in hippocampal neurons. J. Biol. Chem. 281, 28079-28089, Kelly, B.L., Ferreira, A., 2007. Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons. Neuroscience 147, 60-70]. Building on previous reports, these results identified calpain as a potential target for therapeutic intervention in Alzheimer's disease. In the present study, we tested the ability of A-705253, a novel water-soluble calpain inhibitor with oral availability and enhanced metabolic stability, to prevent Abeta-induced dynamin 1 and tau cleavage in cultured hippocampal neurons. Quantitative Western blot analysis indicated that the incubation of these cells with A-705253 prior to the addition of oligomeric Abeta reduced both dynamin 1 and tau cleavage in a dose-dependent manner. In addition, our results showed that this calpain inhibitor significantly ameliorated the cleavage of these proteins when added simultaneously with oligomeric Abeta. Furthermore, our data indicated that the use of this calpain inhibitor could have some beneficial effects even when added after the cleavage of these proteins have been triggered by Abeta. Collectively, these results suggest that, indeed, specific calpain inhibitors could play an important role in the treatment of Alzheimer's disease.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Benzamidas/farmacología , Calpaína/metabolismo , Dinamina I/metabolismo , Neuronas/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/toxicidad , Animales , Benzamidas/uso terapéutico , Western Blotting , Calpaína/antagonistas & inhibidores , Células Cultivadas , Dimerización , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Hipocampo/citología , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Ratas
4.
ACS Med Chem Lett ; 9(3): 221-226, 2018 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-29541364

RESUMEN

Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1' modified calpain inhibitors with significantly improved pharmacokinetic profile including P1' N-methoxyamide 23 as potential candidate compound for non-central nervous system indications.

5.
J Med Chem ; 60(16): 7123-7138, 2017 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-28759231

RESUMEN

Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Aminobutiratos/farmacología , Calpaína/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Pirazoles/farmacología , Aminobutiratos/síntesis química , Aminobutiratos/farmacocinética , Animales , Catepsinas , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Perros , Hipocampo/metabolismo , Humanos , Concentración 50 Inhibidora , Macaca fascicularis , Masculino , Microsomas Hepáticos/metabolismo , Niacinamida/síntesis química , Niacinamida/farmacocinética , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Ratas Wistar , Sueño REM/efectos de los fármacos , Espectrina/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
6.
Neuropsychopharmacology ; 41(4): 979-88, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26216521

RESUMEN

Preclinical studies revealed contribution of N-methyl-D-aspartate receptors (NMDARs) to a variety of neuropsychiatric diseases including alcoholism, but development of NMDAR antagonists for therapeutic use has been a challenge, in part due to severe side effects. One of the key intracellular events resulting from stimulation of NMDAR is activation of calpains-calcium-dependent cysteine proteases. Here we studied whether inhibition of calpains would produce therapeutic-like effects of NMDAR antagonists but without their NMDAR-mediated side-effect profile. The calpain inhibitor A-705253 (3-10 mg/kg) was tested in a model of cue-induced reinstatement of alcohol-seeking behavior in post-dependent Wistar rats and in an alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats, two behavioral models for alcohol-seeking and relapse, respectively. We also tested the effect of A-705253 on the saccharine deprivation effect (SDE) as a selectivity measure. Acute treatment with A-705253 dose-dependently reduced cue-induced reinstatement of alcohol-seeking behavior. Repeated administration of A-705253 caused significant reductions of relapse-like excessive alcohol intake during the post-abstinence drinking days, an effect that persisted during two more successive drug-free drinking weeks, which was selective for the ADE as the SDE was unaffected. However, A-705253 did not produce psychostimulant, cognition impairing (delayed-matching-to-position), or psychotomimetic effects (specifically, phencyclidine discriminative stimulus effects). Taken together, these results demonstrate the involvement of calpains in alcohol-seeking and relapse and present a rationale for a novel pharmacological intervention that may reduce craving and relapse with minimal side effects in alcohol-dependent patients.


Asunto(s)
Benzamidas/administración & dosificación , Calpaína/fisiología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Etanol/administración & dosificación , Animales , Benzamidas/efectos adversos , Calpaína/antagonistas & inhibidores , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Señales (Psicología) , Ratas , Ratas Wistar , Recurrencia , Sacarina/administración & dosificación , Autoadministración
7.
Neuropharmacology ; 101: 358-69, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26471422

RESUMEN

The GABA(B) receptor has been indicated as a promising target for multiple CNS-related disorders. Baclofen, a prototypical orthosteric agonist, is used clinically for the treatment of spastic movement disorders, but is associated with unwanted side-effects, such as sedation and motor impairment. Positive allosteric modulators (PAM), which bind to a topographically-distinct site apart from the orthosteric binding pocket, may provide an improved side-effect profile while maintaining baclofen-like efficacy. GABA, the major inhibitory neurotransmitter in the CNS, plays an important role in the etiology and treatment of seizure disorders. Baclofen is known to produce anticonvulsant effects in the DBA/2J mouse audiogenic seizure test (AGS), suggesting it may be a suitable assay for assessing pharmacodynamic effects. Little is known about the effects of GABA(B) PAMs, however. The studies presented here sought to investigate the AGS test as a pharmacodynamic (PD) screening model for GABA(B) PAMs by comparing the profile of structurally diverse PAMs to baclofen. GS39783, rac-BHFF, CMPPE, A-1295120 (N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide), and A-1474713 (N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide) all produced robust, dose-dependent anticonvulsant effects; a similar profile was observed with baclofen. Pre-treatment with the GABA(B) antagonist SCH50911 completely blocked the anticonvulsant effects of baclofen and CMPPE in the AGS test, indicating such effects are likely mediated by the GABA(B) receptor. In addition to the standard anticonvulsant endpoint of the AGS test, video tracking software was employed to assess potential drug-induced motor side-effects during the acclimation period of the test. This analysis was sensitive to detecting drug-induced changes in total distance traveled, which was used to establish a therapeutic index (TI = hypoactivity/anticonvulsant effects). Calculated TIs for A-1295120, CMPPE, rac-BHFF, GS39783, and A-1474713 were 5.31x, 5.00x, 4.74x, 3.41x, and 1.83x, respectively, whereas baclofen was <1. The results presented here suggest the DBA/2J mouse AGS test is a potentially useful screening model for detecting PD effects of GABA(B) PAMs and can provide an initial read-out on target-related motor side-effects. Furthermore, an improved TI was observed for PAMs compared to baclofen, indicating the PAM approach may be a viable therapeutic alternative to baclofen.


Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Baclofeno/uso terapéutico , Convulsiones/tratamiento farmacológico , Estimulación Acústica/efectos adversos , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Animales , Animales Recién Nacidos , Ciclopentanos/farmacología , Interacciones Farmacológicas , Agonistas del GABA/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Masculino , Ratones , Ratones Endogámicos DBA , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Convulsiones/etiología , Isótopos de Azufre/farmacocinética
8.
Neuropharmacology ; 63(4): 606-12, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22613839

RESUMEN

Calcium-mediated pathologic activation of the cysteine protease calpain has been linked to neurodegenerative disorders such as Alzheimer's disease (AD) through the cleavage of proteolytic substrates that negatively affect neuronal function. Hyperphosphorylation of the microtubule-associated protein tau and the subsequent aggregation of tau filaments resulting in the intracellular formation of neurofibrillary tangles are recognized as key etiological factors in AD pathology. Cyclin-dependent kinase 5 (Cdk5), a major kinase responsible for tau hyperphosphorylation in the AD brain, becomes hyperactivated through calpain-mediated cleavage-conversion of the Cdk5 regulatory protein p35 to p25. In the present study, we examined the effects of the novel small-molecule calpain inhibitor A-705253 in acute models of tau hyperphosphorylation in vitro and in vivo. In hippocampal slices in vitro, lowering medium temperature to 33 °C increased tau phosphorylation in which incubation with A-705253 blocked low temperature-induced tau phosphorylation as measured by Western blot analysis. Pentobarbital-induced hypothermia or acute systemic LPS treatment in normal mice increased tau phosphorylation in hippocampal CA3 mossy fibers, as measured by immunohistochemistry, whereas acute A-705253 pretreatment prevented the stress-induced tau hyperphosphorylation in both models. In support of a Cdk5-mediated mechanism, A-705253 administered for two weeks in the drinking water of six month-old prepathogenic 3x Tg-AD mice resulted in decreased expression of the calpain proteolytic p25 fragment. Taken together, results of these studies suggest that calpain inhibition has potential utility in reducing tau hyperphosphorylation and may represent a novel disease-modifying approach in the treatment of AD.


Asunto(s)
Benzamidas/farmacología , Calpaína/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Proteínas tau/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Animales , Benzamidas/uso terapéutico , Calpaína/metabolismo , Frío/efectos adversos , Inhibidores de Cisteína Proteinasa/uso terapéutico , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos , Ratones Transgénicos , Terapia Molecular Dirigida , Fibras Musgosas del Hipocampo/efectos de los fármacos , Fibras Musgosas del Hipocampo/metabolismo , Neuronas/metabolismo , Neuronas/patología , Fragmentos de Péptidos/metabolismo , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos
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