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1.
Bioorg Med Chem Lett ; 47: 128202, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34139325

RESUMO

Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.


Assuntos
Aorta/metabolismo , Tratamento Farmacológico da COVID-19 , Catepsina C/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Síndrome do Desconforto Respiratório/tratamento farmacológico , Acetonitrilas/química , Acetonitrilas/farmacologia , Aminoácidos/química , Aminoácidos/farmacologia , Compostos de Bifenilo/farmacologia , COVID-19/complicações , Humanos , Modelos Moleculares , Estrutura Molecular , Síndrome do Desconforto Respiratório/etiologia , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 28(23-24): 3766-3773, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30340896

RESUMO

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: <15 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.


Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tetrazóis/química , Tetrazóis/farmacologia , Administração Oral , Aldeído Oxirredutases/metabolismo , Animais , Fumar Cigarros/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Relação Estrutura-Atividade , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética
3.
Bioorg Med Chem Lett ; 28(7): 1211-1218, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29519738

RESUMO

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 160-950 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: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg).


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Furanos/farmacologia , Imidazóis/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular Tumoral , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Furanos/administração & dosagem , Furanos/química , Cobaias , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/administração & dosagem , Imidazóis/química , Macaca fascicularis , Estrutura Molecular , Dor/tratamento farmacológico , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 27(23): 5131-5138, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29100801

RESUMO

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 <50 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 14.3 mg/kg in guinea pig.


Assuntos
Inibidores Enzimáticos/química , Furanos/química , Imidazóis/química , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Administração Oral , Animais , Cães , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Cobaias , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Concentração Inibidora 50 , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Prostaglandina-E Sintases/metabolismo , Ratos , Solubilidade , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 27(11): 2594-2601, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28400234

RESUMO

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.


Assuntos
Imidazóis/química , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Administração Oral , Animais , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Cobaias , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Concentração Inibidora 50 , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 26(24): 5977-5984, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27865703

RESUMO

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.


Assuntos
Benzimidazóis/farmacologia , Dioxanos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Dioxanos/síntese química , Dioxanos/química , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cobaias , Temperatura Alta , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 24(20): 4838-44, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25260492

RESUMO

mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE2. Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs (28, 48, 49) were identified with <10nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE2 biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib.


Assuntos
Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Pirimidinonas/farmacologia , Quinazolinonas/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Oxirredutases Intramoleculares/metabolismo , Estrutura Molecular , Prostaglandina-E Sintases , Pirimidinonas/síntese química , Pirimidinonas/química , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 23(24): 6747-54, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24231362

RESUMO

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.


Assuntos
Imidazóis/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Tiazóis/química , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Meia-Vida , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêutico
9.
Bioorg Med Chem Lett ; 22(19): 6286-91, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22944118

RESUMO

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.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Doença de Parkinson/tratamento farmacológico , Piridonas/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Imidazóis/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Doença de Parkinson/enzimologia , Doença de Parkinson/metabolismo , Piridonas/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 22(9): 3223-8, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22487174

RESUMO

The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacologia , Pirimidinonas/farmacologia , Sistema Nervoso Central , Humanos , Isoxazóis/química , Doença de Parkinson/tratamento farmacológico , Farmacocinética , Inibidores de Fosfodiesterase/química , Pirimidinonas/química , Relação Estrutura-Atividade , Tiazóis/química
11.
Auton Neurosci ; 166(1-2): 35-8, 2012 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-22037502

RESUMO

PURPOSE: To evaluate the effect of a transient receptor potential vanilloid 1 (TRPV1) antagonist GRC 6211 on neurogenic detrusor overactivity (NDO) of spinal origin. MATERIALS AND METHODS: Cystometries under urethane anaesthesia were obtained in 14 chronic spinalized rats to confirm NDO. Two groups were created. In the first one (n=10), GRC 6211 (0.01, 0.1 and 1mg/kg weight) was administered via the duodenum in cumulative doses and cystometries performed 150 min after the administration of each dose of the drug. In the second group (n=4), used as control, the animals were submitted to cystometries during 12 hours, without administration of GRC 6211. Frequency and amplitude of bladder contractions were recorded in both groups. RESULTS: The mean (±SDev) bladder detrusor muscle contraction frequency of spinalized rats was 0.7±0.27 contractions/min. GRC 6211 produced a significant dose-dependent effect, with the frequency diminished to 0.53±0.23, 0.40±0.20 and 0.20±0.13 contractions/min, respectively. The mean (± SDev) amplitude of bladder contractions was 48.4±4.4 cmH(2)O. After administration of 0.01 mg/kg, 0.1mg/kg and 1mg/kg of GRC 6211, the amplitude decreased to 47.1±4.3, 45.6±5.6 and 40.2±4.1 cm H(2)O respectively. The effect was significant at 0.1 and 1mg/kg doses. Cystometries performed in the control group of spinalized rats showed no evidence of detrusor fatigue caused by the urethane anaesthesia and long duration of the experiment. CONCLUSION: TRPV1 antagonists may be very effective in reducing NDO of spinal origin. This finding may have profound implications for the pathogenesis and future treatment options of patients with spinal NDO.


Assuntos
Músculo Liso/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/inervação , Músculo Liso/fisiopatologia , Pressão , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/complicações , Canais de Cátion TRPV/fisiologia , Resultado do Tratamento , Ureia/farmacologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinaria Neurogênica/fisiopatologia , Urodinâmica/efeitos dos fármacos , Urodinâmica/fisiologia
12.
Eur J Med Chem ; 45(9): 3709-18, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20627471

RESUMO

A series of novel dibenzo[b,d]furan mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit Protein Tyrosine Phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Structure-activity relationship study led to the identification of potent compound 5 E which inhibited PTP1B with IC(50) value of 82+/-0.43 nM. Compound 5 E was screened in vivo as drug candidate for anti-diabetic activity using rosiglitazone maleate as the standard. Compound 5 E showed significant reduction in body weight, fed-state whole blood glucose (WBG), fasting WBG, plasma glucose and plasma cholesterol levels and non-significant reduction in fasting plasma triglyceride levels in ob/ob mice.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Furanos/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ácidos Carboxílicos/química , Domínio Catalítico , Colesterol/sangue , Descoberta de Drogas , Hipoglicemiantes/química , Concentração Inibidora 50 , Masculino , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Especificidade por Substrato , Triglicerídeos/sangue
13.
Eur J Med Chem ; 44(8): 3147-57, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19349096

RESUMO

A series of novel isochroman mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Analysis of structure-activity relationships led to the identification of potent compound 4n which inhibited PTP1B with IC(50) value of 51.63+/-0.91 nM. In general, high potency was associated with a dithiolane ring with a spacer of five carbons to the isochroman ring. Compound 4n has been selected for in vivo evaluation as drug candidate for anti-diabetic activity.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Desenho de Fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Animais , Ácidos Carboxílicos/química , Hipoglicemiantes/química , Concentração Inibidora 50 , Masculino , Camundongos , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade
14.
J Urol ; 181(1): 379-86, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19010489

RESUMO

PURPOSE: We evaluated the effects of GRC-6211, an orally active TRPV1 antagonist, on the function and noxious input of naïve and inflamed bladders. MATERIALS AND METHODS: In urethane (Sigma(R)) anesthetized rats 0.5 ml GRC-6211 (0.001, 0.01, 0.1 and 1 mg/kg weight) or its vehicle (0.5% methylcellulose) were administered through a duodenal catheter and cystometry was done during infusion of saline, 100 microM capsaicin or 0.5% acetic acid (Merck, Feltham, United Kingdom). Cystometry was also performed in WT and TRPV1 knockout mice treated with 1 mg/kg GRC-6211. Cystometry was done in rats inflamed with lipopolysaccharide after receiving 0.1 mg/kg GRC-6221 or vehicle. Spinal c-fos expression induced by 0.5% acetic acid was investigated after 0.1 mg/kg GRC-6211 or vehicle administration. TRPV1 immunoreactivity was evaluated in the bladder after GRC-6211 administration. RESULTS: The reflex activity of rat and WT mice naïve bladders was unchanged by GRC-6211 up to a dose of 0.1 mg/kg. At 1 mg/kg contractions were transiently suppressed in naïve rats and WT mice but not in TRPV1 knockout mice. GRC-6211 (0.1 mg/kg) completely prevented capsaicin induced irritation, while the 0.001, 0.01 or 0.1 mg/kg dose decreased the mean +/- SD frequency of bladder contractions during acetic acid infusion from 1.5 +/- 0.3 to 1.35 +/- 0.35 (not significant), 0.9 +/- 0.2 (p <0.05) and 0.8 +/- 0.2 (p <0.05), respectively. Lipopolysaccharide inflamed rats had 1.4 +/- 0.4 and 0.8 +/- 0.1 contractions per minute after vehicle and GRC-6211, respectively (p <0.05). The c-fos expression induced by acetic acid was decreased by GRC-6211 (85.5 +/- 19.1 to 46.7 +/- 9.4, p <0.05). GRC-6211 did not change bladder TRPV1 immunoreactivity. CONCLUSIONS: GRC-6211 counteracts the bladder hyperactivity and noxious input induced by cystitis. At high doses it suppresses normal bladder activity by a TRPV1 dependent mechanism. TRPV1 antagonists might be useful for cystitis.


Assuntos
Cistite/prevenção & controle , Canais de Cátion TRPV/antagonistas & inibidores , Bexiga Urinária Hiperativa/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Ratos , Ratos Wistar , Bexiga Urinária/efeitos dos fármacos
15.
Expert Opin Drug Discov ; 4(2): 159-80, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23480514

RESUMO

BACKGROUND: The capsaicin receptor TRPV1, a polymodal nociceptor whose expression is up-regulated in a number of painful inflammatory disorders, represents a promising therapeutic target for pain relief. Potent small molecule TRPV1 antagonists are now undergoing clinical trials in patients with inflammatory or neuropathic pain. This review focuses on the multiplicity of factors regulating this channel and on their contributions to the emerging complexity of responses to TRPV1 and partial antagonists. For example, it is now clear that antagonists of capsaicin response can also antagonize, have no effect, or stimulate response to heat or protons. The complexity of TRPV1 regulation affords the potential to optimize agents for a specific therapeutic indication. An encouraging advance is the dissection of therapeutic efficacy of antagonists from induction of hyperthermia, a side effect that initially had raised concerns about the suitability of systemically administered TRPV1 antagonists for therapy. OBJECTIVES AND METHODS: To discuss the challenges facing the development of clinically useful TRPV1 antagonists based on our experience and a comprehensive review of the literature. RESULTS/CONCLUSIONS: TRPV1 is a polymodal receptor. Some antagonists block all modalities of TRPV1 stimulation whereas others are more selective in their pharmacological profile. A number of antagonists can, conversely, potentiate certain modes of TRPV1 activation (e.g., protons and heat). The selectivity of TRPV1 antagonists is species-dependent, posing a problem for extrapolation from animal models to patients. At present, this rich pharmacology of TRPV1 antagonists complicates drug development but for the future it promises great opportunities for drug design.

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