RESUMEN
Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation.
Asunto(s)
Fenindiona/análogos & derivados , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Cristalografía por Rayos X , Activación Enzimática , Enlace de Hidrógeno , Isomerismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fenindiona/farmacología , Fosforilación , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema.
Asunto(s)
Amidas/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Glicina/farmacología , Óxido Nítrico/química , Ácido Acético , Amidas/química , Animales , Carragenina , Línea Celular , Constricción Patológica/inducido químicamente , Constricción Patológica/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa 2/química , Edema/inducido químicamente , Edema/tratamiento farmacológico , Glicina/análogos & derivados , Glicina/química , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hígado/metabolismo , Masculino , Ratones , Nitratos/metabolismo , Nitritos/metabolismo , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules.
Asunto(s)
Analgésicos/química , Analgésicos/uso terapéutico , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Pirroles/química , Pirroles/uso terapéutico , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Masculino , Ratones , Dolor/tratamiento farmacológico , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
The aim of this in vitro study was to examine the possible effect of [2-methyl-5-(4-methylsulphonyl)phenyl-1-phenyl-3-(2-n-propyloxyethyl)]-1H-pyrrole (VA441), a new selective cyclooxygenase (COX)-2 inhibitor, on human osteoarthritic (OA) chondrocyte cultivated in the presence or absence of interleukin-1ß (IL-1ß). In particular, we assessed the effects of 1 and 10 µM of VA441, celecoxib, and indomethacin on cell viability, COX-2 and inducible nitric oxide synthase (iNOS) gene expression, prostaglandin E(2) (PGE(2)) production, and nitric oxide (NO) and metalloproteinase-3 (MMP-3) release. Furthermore, we carried out morphological assessment by transmission electron microscopy (TEM). The presence of IL-1ß led to a significant increase in PGE(2), MMP-3, and NO production, as well as a significant increase in gene expression of COX-2 and iNOS. All the drugs tested had a statistically significant inhibitory effect on PGE(2) production and gene expression of COX-2 stimulated by IL-1ß. VA441 and celecoxib significantly suppressed IL-1ß-stimulated MMP-3 and NO and iNOS gene expression in a dose-dependent manner, while indomethacin did not show any significant effect on MMP-3 and NO production or on iNOS gene expression. TEM demonstrated that IL-1ß severely alters the structure of chondrocytes; after co-incubation with VA441 or celecoxib, the cells recovered their ultrastructure. Our data suggest that VA441 and celecoxib may have a beneficial effect on chondrocyte metabolism.
Asunto(s)
Condrocitos/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Pirroles/farmacología , Sulfonas/farmacología , Anciano , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/metabolismo , Ciclooxigenasa 2/genética , Dinoprostona/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta/farmacología , Metaloproteinasa 3 de la Matriz/metabolismo , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , OsteoartritisRESUMEN
Translocator protein 18 kDa [TSPO or peripheral-type benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.
Asunto(s)
Benzodiazepinas/farmacología , Compuestos de Boro/metabolismo , Mitocondrias/efectos de los fármacos , Receptores de GABA/metabolismo , Benzodiazepinas/química , Química Farmacéutica , Humanos , Ligandos , Mitocondrias/metabolismo , Estructura Molecular , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Receptores de GABA/genéticaRESUMEN
This review discusses the rational for further studies of COX-2 inhibitors-NO releaser hybrids (NO-Coxibs) in the pharmacological treatment of the airway inflammation in Cystic Fibrosis (CF). Our research group developed several classes of NO-Coxibs for the pharmacological treatment of arthritis, and among them several compounds showed an outstanding in vivo efficacy and good pharmacokinetic properties. The good antiinflammatory properties displayed by these compounds during the previous screening could, by itself, suggest appropriate candidates for further testing in CF.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Fibrosis Quística/tratamiento farmacológico , Óxido Nítrico/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Fibrosis Quística/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Estructura Molecular , Óxido Nítrico/químicaRESUMEN
Supramolecular complexes consisting of a hydrophobic dendrimer host [DAB-dendr-(NHCONH-Ad)(64)] as well as solubilizing and bioactive guest molecules have been synthesized using a noncovalent approach. The guest-host supramolecular assembly is first preassembled in chloroform and transferred via the neat phase to aqueous solution. The bioactive guest molecules can bind to a natural (serotonin 5-HT(3)) receptor with nanomolar affinity as well as to the synthetic dendrimer receptor in aqueous solution, going toward a dynamic multivalent supramolecular construct capable of adapting itself to a multimeric receptor motif.
Asunto(s)
Dendrímeros/química , Dendrímeros/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Agua/química , Humanos , Espectroscopía de Resonancia Magnética , Agua/metabolismoRESUMEN
Novel AT 1 receptor antagonists bearing the pyrazolo[3,4- b]pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The preliminary pharmacological characterization revealed nanomolar AT 1 receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a. These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high. Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter. These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT 1 receptor antagonists.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Compuestos Bicíclicos Heterocíclicos con Puentes , Pirazoles , Piridinas , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/síntesis química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Mucosa Intestinal/efectos de los fármacos , Masculino , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Conejos , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Following our previous research on anti-inflammatory drugs (NSAIDs), we report here the synthesis of chiral 1,5-diarylpyrroles derivatives that were characterized for their in vitro inhibitory effects toward cyclooxygenase (COX) isozymes. Analysis of enzymatic affinity and COX-2 selectivity led us to the selection of one compound (+/-)-10b that was further tested in vitro in the human whole blood (HWB) and in vivo for its anti-inflammatory activity in mice. The affinity data have been rationalized through docking simulations.
Asunto(s)
Alcoholes/química , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Éteres/química , Modelos Químicos , Pirroles/farmacología , Ácido Acético , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Sitios de Unión , Carragenina , Células Cultivadas , Simulación por Computador , Ciclooxigenasa 1/efectos de los fármacos , Ciclooxigenasa 2/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Isoenzimas/efectos de los fármacos , Masculino , Ratones , Estructura Molecular , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Pirroles/síntesis química , Pirroles/química , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Selective cyclooxigenase (COX)-2 inhibitors were developed to prevent traditional non-steroidal anti-inflammatory drugs (tNSAIDs) gastro-intestinal adverse effects. VA692, a recently disclosed selective COX-2 inhibitor, structurally related to well-known marketed coxibs, showed anti-inflammatory, and anti-nociceptive properties. The aim of this study was to analyze the anti-inflammatory effect of VA692, in comparison with celecoxib. At this purpose we evaluated the pro-inflammatory cytokines and anti-oxidant enzymes gene expression, apoptosis and ROS production, and PGE2 release in chondrocytes (both primary cultures and immortalized T/C-28a2 cell line) treated with the two drugs. Furthermore, a proteomic analysis has been performed in T/C-28a2 cell line to evaluate modifications in their proteomic profile following drug treatment in presence of IL-1ß. Our results demonstrated the anti-inflammatory effect of the novel synthesized VA692, and confirmed those of celecoxib, in counteracting the stimulus of IL-1ß in both osteoarthritic (OA) chondrocytes and T/C-28a2 cell line. Furthermore, the data underlined the possible anti-apoptotic and anti-oxidant role of VA692, implying its regulation in superoxide anion production as indicated by the modulation of anti-oxidant enzymes. The proteomic analysis provides new information about the effect of VA692 on human T/C-28a2 intracellular proteome, demonstrating the usefulness of this approach in the identification and quantifications of several proteins. Modulation of some proteins such as Hsp90 and SOD by VA692 could explain its role in the therapeutic approach of OA. Based on our results, we can affirm that VA692 has more beneficial effect compared with celecoxib particularly regarding the modulation of oxidant/anti-oxidant system and proteome profile of human articular chondrocytes.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Osteoartritis/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Celecoxib/farmacología , Células Cultivadas , Condrocitos/efectos de los fármacos , Humanos , Interleucina-1beta/farmacología , Proteómica , Superóxido Dismutasa-1/análisisRESUMEN
Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate- and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na+ and Ca2+-channels, showing a profile comparable with that of 1.
Asunto(s)
Fármacos Neuroprotectores/síntesis química , Tiazinas/farmacología , Animales , Encéfalo/patología , Canales de Calcio/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Ácido Glutámico/deficiencia , Humanos , Neuroblastoma/patología , Fármacos Neuroprotectores/farmacología , Oxígeno/metabolismo , Especies Reactivas de Oxígeno , Tiazinas/síntesis química , Canales de Sodio Activados por Voltaje/efectos de los fármacosRESUMEN
A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Pirroles/química , Pirroles/uso terapéutico , Adulto , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Edema/tratamiento farmacológico , Halogenación , Humanos , Hiperalgesia/tratamiento farmacológico , Modelos Moleculares , Pirroles/síntesis química , Ratas , Piel/efectos de los fármacos , Piel/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
The increasing prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) worldwide is becoming a challenge for the modern global care system. The lipotoxic process is characterized by an oxidative stress followed by a burst of the inflammatory response, prompting the wound healing process (fibrosis), which can ultimately lead to the development of cirrhosis and the subsequent complications. There is no consensus concerning an effective pharmacological treatment. Therefore, there is a need for effective therapeutic compounds. Silibinin the major active compound of Milk Thistle may be a potential candidate mainly due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. In spite of the large number of data obtained in experimental models, the translation of the evidence in clinical setting is far to be conclusive. The aim of this paper is to critically review the aspects of the use of the different formulations of Silibinin in several experimental and clinical settings and to provide hints on the needed future studies.
Asunto(s)
Antioxidantes/uso terapéutico , Hepatopatías/tratamiento farmacológico , Silimarina/uso terapéutico , Administración Oral , Animales , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Humanos , Hepatopatías/metabolismo , Silimarina/química , Silimarina/farmacocinética , Silimarina/farmacologíaRESUMEN
VA694, a promising cyclooxigenase-2 (COX-2)-inhibiting hybrid drug endowed with nitric oxide (NO) releasing properties (NO-COXIB), showed COX-2-selective inhibitory effects, associated with interesting anti-inflammatory and anti-nociceptive activities. Therefore, we studied the effects of VA694 on cartilage metabolism, in comparison with Naproxcinod, a COX inhibitor and NO donor (CINOD), and Naproxen, a traditional non-steroidal-anti-inflammatory drug (NSAID) on human osteoarthritic chondrocyte cultures. IL-1ß-stimulated chondrocytes showed a significant decrease in cell viability (P<0.001). VA694, Naproxcinod and Naproxen alone didn't significantly affect cell viability, while it restored cell viability in cultures stimulated by IL-1ß. The presence of IL-1ß determined a significant increase (P<0.001) in PGE2 levels measured by an ELISA assay, and in COX-2 and MMP-3, -9, and -13 gene expression analyzed by RT-PCR. VA694, Naproxcinod and Naproxen, at both concentrations analyzed, significantly counteracted the negative effects induced by IL-1ß. VA694, Naproxcinod and Naproxen pre-treatment were able to inhibit IL-1ß-induced NF-κB activation, when measured as its nuclear translocation (p50 and p65 subunits). Naproxcinod and Naproxen pre-treatment didn't affect cytoplasmic NF-κB levels; VA694 decreased the cytoplasmic levels of both subunits. Our data suggest that VA694, Naproxcinod and Naproxen, exert anti-inflammatory and chondroprotective effects on OA chondrocytes.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Condrocitos/efectos de los fármacos , Interleucina-1beta/farmacología , Naproxeno/análogos & derivados , Nitratos/farmacología , Osteoartritis de la Cadera/inmunología , Pirroles/farmacología , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/inmunología , Ciclooxigenasa 2/genética , Dinoprostona/análisis , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasas de la Matriz/genética , Persona de Mediana Edad , Estructura Molecular , FN-kappa B/inmunología , Naproxeno/química , Naproxeno/farmacología , Nitratos/química , Pirroles/químicaRESUMEN
A novel potent and selective kynurenine-3-hydroxylase inhibitor is descibed along a preliminary evaluation in a in vivo gerbil model of its ability to increase the kynurenine and kynurenic acid concentration in both plasma and brain. These data support the notion that kynurenine-3-hydroxylase inhibitors may have a sustained therapeutic potential in those diseases characterized by unbalance in the QUIN/KYNA branches of the kynurenine pathway.
Asunto(s)
Quinurenina/metabolismo , Oxigenasas de Función Mixta/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Triptófano/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Gerbillinae , Humanos , Técnicas In Vitro , Quinurenina 3-Monooxigenasa , Oxigenasas de Función Mixta/química , Modelos Moleculares , Fármacos Neuroprotectores/química , Conformación ProteicaRESUMEN
Selective COX-2 inhibitors (COXib) belonging to the class of diaryl heterocycles (e.g., celecoxib, rofecoxib, etc.), are devoid of the undesirable effects due to their capacity to inhibit selectively inducible (COX-2), responsible for inflammatory effects but not constitutive cyclooxygenase-1 (COX-1)(COX); responsible for cytoprotective effects on gastric mucosa. In addition, several reports have identified an increased risk of cardiovascular events associated with the use of COXib. We have developed a new series of anti-inflammatory agents (1,5-diarylpyrrole-3-alkoxyethyl esters and ethers). To evaluate the effect of two 1,5-diarylpyrrole-3-alkoxyethyl ethers, VA441 and VA428 (up to 100 µM), respectively, in comparison with two well known COXib, celecoxib and rofecoxib, on HaCaT cell (keratinocytes) proliferation and toxicity. Crucial molecules in cell cycle progression, i.e. NFκB and ERK as targets/mediators and cyclin D1 and p21 Cip1/Kip as final effectors were evaluated by Western blot, immunohystochemistry and q-PCR analysis. Both compounds, VA441 and VA428, showed a strong inhibition of cell proliferation, and did not exhibit cytotoxicity. The anti-proliferative effect was accompanied by a strong activation of ERK and induction of the cell cycle inhibitor p21. In addition, there was a clear inhibition of the transcription factor NF-κB and downregulation of cyclin D1, with enforced inhibition of the HaCaT cell cycle progression. These data suggest that compounds VA441 and VA428, along with their role in inhibiting COX-2 and inflammation, could have a possible therapeutic (topical and systemic) use against skin proliferative disorders, such as psoriasis.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Pirroles/farmacología , Sulfonas/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclooxigenasa 2/genética , Expresión Génica/efectos de los fármacos , Humanos , Queratinocitos , FN-kappa B/metabolismo , ARN Mensajero/metabolismoRESUMEN
A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
Asunto(s)
Pirrolidinonas/química , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/síntesis química , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Animales , Área Bajo la Curva , Humanos , Absorción Intestinal , Ligandos , Masculino , Tasa de Depuración Metabólica , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Estructura Terciaria de Proteína , Ensayo de Unión Radioligante , Receptores de Serotonina 5-HT3/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Relación Estructura-ActividadRESUMEN
A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1ß (IL-1ß), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Donantes de Óxido Nítrico/farmacología , Pirroles/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/química , Éteres/síntesis química , Éteres/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Osteoartritis/tratamiento farmacológico , Pirroles/síntesis química , Pirroles/química , RatasRESUMEN
The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Constricción Patológica/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico/metabolismo , Ácido Acético , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Carragenina/antagonistas & inhibidores , Carragenina/farmacología , Constricción Patológica/inducido químicamente , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacocinética , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Masculino , Ratones , Estructura Molecular , Músculo Liso Vascular/química , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
In the last decade a considerable effort has been made both by the regulators and the pharmaceutical industry to assess genotoxic impurities (GTI) in pharmaceutical products. Though the control of impurities in drug substances and products is a well established and consolidated procedure, its extension to GTI has given rise to a number of problems, both in terms of setting the limits and detecting these impurities in pharmaceutical products. Several papers have dealt with this issue, discussing available regulations, providing strategies to evaluate the genotoxic potential of chemical substances, and trying to address the analytical challenge of detecting GTI at trace levels. In this review we would like to discuss the available regulations, the toxicological background for establishing limits, as well as the analytical approaches used for GTI assessment. The final aim is that of providing a complete overview of the topic with updated available information, to address the overall GTI issue during the development of new drug substances.