RESUMEN
Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15â¯nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.
Asunto(s)
Aldehído Oxidorreductasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Imidazoles/química , Imidazoles/farmacología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Tetrazoles/química , Tetrazoles/farmacología , Administración Oral , Aldehído Oxidorreductasas/metabolismo , Animales , Fumar Cigarrillos/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Halogenación , Humanos , Imidazoles/administración & dosificación , Imidazoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Relación Estructura-Actividad , Tetrazoles/administración & dosificación , Tetrazoles/farmacocinéticaRESUMEN
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950â¯nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6â¯mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106â¯mg/kg).
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores Enzimáticos/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Furanos/farmacología , Imidazoles/farmacología , Prostaglandina-E Sintasas/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular Tumoral , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Furanos/administración & dosificación , Furanos/química , Cobayas , Humanos , Hiperalgesia/tratamiento farmacológico , Imidazoles/administración & dosificación , Imidazoles/química , Macaca fascicularis , Estructura Molecular , Dolor/tratamiento farmacológico , Prostaglandina-E Sintasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50â¯nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3â¯mg/kg in guinea pig.
Asunto(s)
Inhibidores Enzimáticos/química , Furanos/química , Imidazoles/química , Prostaglandina-E Sintasas/antagonistas & inhibidores , Células A549 , Administración Oral , Animales , Perros , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Cobayas , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Concentración 50 Inhibidora , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Prostaglandina-E Sintasas/metabolismo , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.
Asunto(s)
Imidazoles/química , Prostaglandina-E Sintasas/antagonistas & inhibidores , Células A549 , Administración Oral , Animales , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Cobayas , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Imidazoles/síntesis química , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Concentración 50 Inhibidora , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Prostaglandina-E Sintasas/genética , Prostaglandina-E Sintasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d {2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8nM), cell (A549 IC50: 16.24nM) and human whole blood potency (IC50: 249.9nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7mg/kg, respectively.
Asunto(s)
Bencimidazoles/farmacología , Dioxanos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Prostaglandina-E Sintasas/antagonistas & inhibidores , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Dioxanos/síntesis química , Dioxanos/química , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Cobayas , Calor , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Prostaglandina-E Sintasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of "chemosensor", detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.
RESUMEN
We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng · h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Piridonas/síntesis química , Piridonas/farmacología , Acetatos/síntesis química , Acetatos/farmacocinética , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Área Bajo la Curva , Perros , Diseño de Fármacos , Femenino , Glucurónidos/metabolismo , Macaca fascicularis , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Profármacos , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Piridonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The transient receptor potential canonical (TRPC) channels have gained interest as potential therapeutic targets for respiratory diseases, neurological disorders, cardiovascular disorders, pain, cancer and several other pathological conditions. The TRPC receptor family consists of seven isoforms (C1-C7) and has been divided into three subfamilies based on structural and functional similarities. Several pharmaceutical companies and academic institutes are currently exploring the potential of these nonselective cation channels as therapeutic targets using small molecule inhibitors or modulators. This review covers patents on TRPC receptor modulators published from 2002 to 2014. The review mainly focuses on TRPC receptor target biology, small and large molecule modulators and their therapeutic potential.
Asunto(s)
Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Humanos , Patentes como Asunto , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidoresRESUMEN
We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.
Asunto(s)
Diseño de Fármacos , Éteres/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazinas/farmacología , Piridinas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Éteres/administración & dosificación , Éteres/química , Haplorrinos , Humanos , Masculino , Ratones , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Pirazinas/administración & dosificación , Pirazinas/química , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Cough is a protective reflex action that helps clear the respiratory tract which is continuously exposed to airborne environmental irritants. However, chronic cough presents itself as a disease in its own right and despite its global occurrence; the molecular mechanisms responsible for cough are not completely understood. Transient receptor potential ankyrin1 (TRPA1) is robustly expressed in the neuronal as well as non-neuronal cells of the respiratory tract and is a sensor of a wide range of environmental irritants. It is fast getting acceptance as a key biological sensor of a variety of pro-tussive agents often implicated in miscellaneous chronic cough conditions. In the present study, we demonstrate in vitro direct functional activation of TRPA1 receptor by citric acid which is routinely used to evoke cough in preclinical and clinical studies. We also show for the first time that a potent and selective TRPA1 antagonist GRC 17536 inhibits citric acid induced cellular Ca(+2) influx in TRPA1 expressing cells and the citric acid induced cough response in guinea pigs. Hence our data provides a mechanistic link between TRPA1 receptor activation in vitro and cough response induced in vivo by citric acid. Furthermore, we also show evidence for TRPA1 activation in vitro by the TLR4, TLR7 and TLR8 ligands which are implicated in bacterial/respiratory virus pathogenesis often resulting in chronic cough. In conclusion, this study highlights the potential utility of TRPA1 antagonist such as GRC 17536 in the treatment of miscellaneous chronic cough conditions arising due to diverse causes but commonly driven via TRPA1.
Asunto(s)
Antitusígenos/farmacología , Canales de Calcio/metabolismo , Tos/tratamiento farmacológico , Tos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Antitusígenos/uso terapéutico , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Ácido Cítrico/farmacología , Tos/inducido químicamente , Cobayas , Humanos , Ligandos , Masculino , Canal Catiónico TRPA1 , Receptores Toll-Like/metabolismoRESUMEN
We report analogue-based rational design and synthesis of two novel series of polycyclic heteroarenes, pyrrolo[3,2-b]quinolines and pyrido[2,3-b]indoles, tethered to a biaryl system by a methyl-, ethyl- or propyl ether as PDE10A inhibitors. A number of analogues were prepared with variable chain length and evaluated for their ability to block PDE10A enzyme using a radiometric assay. Detailed SAR analyses revealed that compounds with an ethyl ether linker are superior in potency compared to compounds with methyl or propyl ether linkers. These compounds, in general, showed poor metabolic stability in rat and human liver microsomes. The metabolic profile of one of the potent compounds was studied in detail to identify metabolic liabilities of these compounds. Structural modifications were carried out that resulted in improved metabolic stability without significant loss of potency.
Asunto(s)
Indoles/química , Indoles/farmacología , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolinas/química , Quinolinas/farmacología , Animales , Diseño de Fármacos , Humanos , Indoles/síntesis química , Indoles/metabolismo , Microsomas Hepáticos/metabolismo , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/metabolismo , Quinolinas/síntesis química , Quinolinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.
Asunto(s)
Imidazoles/química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , Tiazoles/química , Animales , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Modelos Animales de Enfermedad , Maleato de Dizocilpina/toxicidad , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Femenino , Semivida , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Trastornos Psicóticos/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/uso terapéuticoRESUMEN
A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9nM) showed a good pharmacokinetic profile upon oral dosing at 10mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.
Asunto(s)
Amidas/química , Analgésicos/síntesis química , Piperidinas/química , Compuestos de Espiro/química , Canales Catiónicos TRPM/antagonistas & inhibidores , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Semivida , Masculino , Ratones , Ratones Endogámicos C57BL , Neuralgia/tratamiento farmacológico , Unión Proteica , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Canales Catiónicos TRPM/metabolismoRESUMEN
The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Piridonas/farmacología , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Imidazoles/química , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/metabolismo , Piridonas/química , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
The transient receptor potential subfamily A member 1 (TRPA1) is a non-selective cation channel implicated in the pathogenesis of several airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Most of the research on TRPA1 focuses on its expression and function in neuronal context; studies investigating non-neuronal expression of TRPA1 are lacking. In the present study, we show functional expression of TRPA1 in human lung fibroblast cells (CCD19-Lu) and human pulmonary alveolar epithelial cell line (A549). We demonstrate TRPA1 expression at both mRNA and protein levels in these cell types. TRPA1 selective agonists like allyl isothiocyanate (AITC), 4-hydroxynonenal (4-HNE), crotonaldehyde and zinc, induced a concentration-dependent increase in Ca+2 influx in CCD19-Lu and A549 cells. AITC-induced Ca+2 influx was inhibited by Ruthenium red (RR), a TRP channel pore blocker, and by GRC 17536, a TRPA1 specific antagonist. Furthermore, we also provide evidence that activation of the TRPA1 receptor by TRPA1 selective agonists promotes release of the chemokine IL-8 in CCD19-Lu and A549 cells. The IL-8 release in response to TRPA1 agonists was attenuated by TRPA1 selective antagonists. In conclusion, we demonstrate here for the first time that TRPA1 is functionally expressed in cultured human lung fibroblast cells (CCD19-Lu) and human alveolar epithelial cell line (A549) and may have a potential role in modulating release of this important chemokine in inflamed airways.
Asunto(s)
Canales de Calcio/metabolismo , Calcio/metabolismo , Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Interleucina-8/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Aldehídos/farmacología , Cationes Bivalentes/metabolismo , Células Cultivadas , Cloruros/farmacología , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Humanos , Interleucina-8/efectos de los fármacos , Isotiocianatos/farmacología , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Rojo de Rutenio/farmacología , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Compuestos de Zinc/farmacologíaRESUMEN
The capsaicin receptor TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is a polymodal nociceptor whose expression is upregulated in several painful disorders. At present, potent small molecule TRPV1 antagonists are undergoing clinical trials in patients with chronic pain. Clinical development of TRPV1 antagonists is, however, facing new challenges. Many drug candidates evoke a febrile reaction that varies among patients. We speculate that TRPV1 gene polymorphism might be an underlying cause of the inter-subject variability in pain sensation and response to TRPV1 antagonists. This newly understood and yet to be fully validated aspect of pain suggests that pain management based on regulating the TRPV1 receptor might require a personalized approach for effective clinical outcome. Here, we provide our perspectives on current progress in targeting TRPV1.