RESUMO
We previously published on the design and synthesis of novel, potent and selective PPARα antagonists suitable for either i.p. or oral in vivo administration for the potential treatment of cancer. Described herein is SAR for a subsequent program, where we set out to identify selective and potent PPARα/δ dual antagonist molecules. Emerging literature indicates that both PPARα and PPARδ antagonism may be helpful in curbing the proliferation of certain types of cancer. This dual antagonism could also be used to study PPARs in other settings. After testing for selective and dual potency, off-target counter screening, metabolic stability, oral bioavailability and associated toxicity, compound 11, the first reported PPARα/δ dual antagonist was chosen for more advanced preclinical evaluation.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Ovarianas/tratamento farmacológico , PPAR alfa/antagonistas & inibidores , PPAR delta/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , PPAR alfa/metabolismo , PPAR delta/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
The discovery and SAR of a novel series of potent and selective PPARα antagonists are herein described. Exploration of replacements for the labile acyl sulfonamide linker led to a biaryl sulfonamide series of which compound 33 proved to be suitable for further profiling in vivo. Compound 33 demonstrated excellent potency, selectivity against other nuclear hormone receptors, and good pharmacokinetics in mouse.
Assuntos
PPAR alfa/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Butiratos/química , Butiratos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Propionatos/química , Propionatos/farmacologia , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Tirosina/análogos & derivados , Tirosina/química , Tirosina/farmacologiaRESUMO
The prostaglandin D(2) (PGD(2)) receptor type 2 (DP2) is a G protein-coupled receptor that has been shown to be involved in a variety of allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. In this study, we describe the preclinical pharmacological and pharmacokinetic properties of the small-molecule DP2 antagonist [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid (AM211). We determine that AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD(2)-stimulated guanosine 5'-O-[γ-thio]triphosphate binding to membranes expressing human DP2. A basophil activation assay and a whole-blood assay of eosinophil shape change were used to demonstrate the ability of AM211 to potently antagonize PGD(2)-stimulated functional responses in relevant human cells and in the context of a physiologically relevant environment. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD(2)-induced leukocytosis in a guinea pig pharmacodynamic assay. AM211 demonstrates efficacy in two animal models of allergic inflammation, including an ovalbumin-induced lung inflammation model in guinea pigs and an ovalbumin-induced mouse model of allergic rhinitis. AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases.
Assuntos
Modelos Animais de Doenças , Compostos de Metilureia/uso terapêutico , Fenilacetatos/uso terapêutico , Antagonistas de Prostaglandina/uso terapêutico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Adulto , Animais , Cães , Feminino , Cobaias , Células HEK293 , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Masculino , Compostos de Metilureia/química , Compostos de Metilureia/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Fenilacetatos/química , Fenilacetatos/farmacologia , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia/metabolismo , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacologia , Ligação Proteica/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/imunologia , Receptores de Prostaglandina/metabolismo , Rinite Alérgica Perene/imunologia , Rinite Alérgica Perene/metabolismoRESUMO
Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing.
Assuntos
Modelos Animais de Doenças , Descoberta de Drogas , Fenilacetatos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Animais , Disponibilidade Biológica , Cães , Camundongos , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/uso terapêutico , RatosRESUMO
Compound 21 (AM432) was identified as a potent and selective antagonist of the DP(2) receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP(2) receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing.
Assuntos
Fenilacetatos/química , Piridinas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Cães , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Inflamação/tratamento farmacológico , Camundongos , Fenilacetatos/farmacocinética , Fenilacetatos/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
Prostaglandin D(2) (PGD(2)) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD(2) is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD(2) and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8+ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4'-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dose-dependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.
Assuntos
Pulmão/efeitos dos fármacos , Muco/metabolismo , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Mucosa Respiratória/efeitos dos fármacos , Fumar/efeitos adversos , Animais , Benzilaminas/farmacocinética , Benzilaminas/farmacologia , Linhagem Celular , Movimento Celular , Feminino , Cobaias , Humanos , Técnicas In Vitro , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Pulmão/imunologia , Pulmão/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Metaplasia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Niacina/análogos & derivados , Niacina/farmacocinética , Niacina/farmacologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologiaRESUMO
A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Indóis/química , Inibidores de Lipoxigenase/química , Proteínas de Membrana/antagonistas & inibidores , Ácidos Pentanoicos/química , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Proteínas de Transporte/metabolismo , Humanos , Indóis/síntese química , Indóis/farmacologia , Leucotrienos/sangue , Leucotrienos/metabolismo , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Modelos Animais , Ácidos Pentanoicos/síntese química , Ácidos Pentanoicos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Indóis/farmacologia , Inflamação/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Propionatos/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase , Doença Aguda , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/enzimologia , Asma/metabolismo , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Extravasamento de Materiais Terapêuticos e Diagnósticos/tratamento farmacológico , Extravasamento de Materiais Terapêuticos e Diagnósticos/enzimologia , Extravasamento de Materiais Terapêuticos e Diagnósticos/metabolismo , Feminino , Humanos , Indóis/uso terapêutico , Inflamação/enzimologia , Inflamação/metabolismo , Leucotrieno B4/biossíntese , Leucotrieno B4/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/tratamento farmacológico , Pneumonia/enzimologia , Pneumonia/metabolismo , Propionatos/uso terapêutico , Ratos , Ratos Sprague-Dawley , ZimosanRESUMO
The synthesis of a series of tricyclic antagonists for the prostaglandin D(2) receptor DP2 (CRTH2) is disclosed. The activities of the compounds were evaluated in a human DP2 binding assay and a human whole blood eosinophil shape change assay. Potential metabolic liabilities of the compounds were addressed through in vitro CYP studies. The lead compound was demonstrated to have efficacy in a mouse model of allergic rhinitis following oral dosing.
Assuntos
Antialérgicos/química , Anti-Inflamatórios/química , Compostos Heterocíclicos com 3 Anéis/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Animais , Antialérgicos/síntese química , Antialérgicos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Camundongos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
Peroxisome-proliferator activated receptors (PPAR) are members of the nuclear hormone receptor superfamily which regulate gene transcription. PPARα is a key regulator of lipid homeostasis and a negative regulator of inflammation. Under conditions of metabolic stress such as fasting or glucose deprivation, PPARα is upregulated in order to control gene expression necessary for processing alternate fuel sources (e.g. fatty acid oxidation) and thereby promote maintenance of cell viability. Clinically, PPARα expression is upregulated in diseased tissues such as melanoma, chronic lymphocytic leukemia, ovarian and prostate cancer. This may allow for cellular proliferation and metastasis. Importantly, genetic knockouts of PPARα have been shown to be protected against tumor growth in a variety of syngeneic tumors models. We hypothesized that a potent and selective PPARα antagonist could represent a novel cancer therapy. Early in our discovery research, we identified NXT629 (Bravo et al., 2014). Herein we describe the pharmacology of NXT629 and demonstrate that it is a potent and selective PPARα antagonist. We identify NXT629 as a valuable tool for use in in vivo assessment of PPARα due to its good systemic exposure following intraperitoneal injection. We explore the in vivo pharmacology of NXT629 and demonstrate that it is efficacious in pharmacodynamic models that are driven by PPARα. Finally, we probe the efficacy of NXT629 in disease models where PPARα knockouts have shown to be protected. We believe that PPARα antagonists will be beneficial in diseases such as ovarian cancer and melanoma where PPARα and fatty acid oxidation may be involved.
Assuntos
Aminopiridinas/farmacologia , PPAR alfa/antagonistas & inibidores , Sulfonamidas/farmacologia , Aminopiridinas/farmacocinética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Camundongos , Metástase Neoplásica , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Sulfonamidas/farmacocinéticaRESUMO
Ibudilast, an asthma drug, has demonstrated antinociceptive effects in several rat models of peripheral neuropathic pain, and a proposed mechanism of action is the inhibition of release of the cytokine tumor necrosis factor-α (TNF-α) from activated spinal microglia. Spinal glial activation has also been demonstrated in rat models of central neuropathic pain following spinal cord injury (SCI). The current study evaluated the effect of a short course of treatment with ibudilast on SCI-induced pain, and for comparison, following a chronic constriction injury (CCI; the Bennett model) of the sciatic nerve in rats. The effects of ibudilast treatment on spinal (SCI and CCI rats), and nerve tissue (CCI only) TNF-α content were also evaluated. Following an acute midthoracic SCI with a microvascular clip (20-g force), hindpaw withdrawal thresholds were significantly decreased, indicating below-level cutaneous tactile hypersensitivity. Likewise, unilateral loose ligation of the sciatic nerve led to a robust ipsilateral tactile hypersensitivity. Rats were treated with either ibudilast (10 mg/kg IP) or vehicle (2 mL/kg) during the period of robust and steady hindpaw hypersensitivity for each model--CCI rats were treated 14-16 days post-surgery, and SCI rats were treated 30-32 days post-surgery--and tested daily. Ibudilast ameliorated hindpaw hypersensitivity in both SCI and CCI rats, whereas vehicle treatment had no effect. Interestingly, repeated treatment led to increased baseline thresholds, beyond the duration of the drug half-life, suggesting persistent changes in neuropathic pain processing. In SCI rats, an increase in TNF-α content in spinal tissue rostral to the SCI was observed. Ibudilast treatment did not significantly alter this increase. In rats with a CCI, TNF-α content was markedly increased in the ipsilateral sciatic nerve and was partially reduced following ibudilast, but not vehicle, treatment. Ibudilast could be useful for the treatment of neuropathic pain of central as well as peripheral origin.
Assuntos
Analgésicos , Antiasmáticos/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Neuralgia/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Piridinas/farmacologia , Animais , Masculino , Neuralgia/etiologia , Neuroglia/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/complicações , Neuropatia Ciática/patologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Compressão da Medula Espinal/complicações , Compressão da Medula Espinal/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB(4) inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC(50) of 76 nM for inhibition of LTB(4) in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Antiasmáticos/síntese química , Indóis/síntese química , Ácidos Pentanoicos/síntese química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacocinética , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Administração Oral , Animais , Antiasmáticos/farmacocinética , Antiasmáticos/farmacologia , Lavagem Broncoalveolar , Inibidores das Enzimas do Citocromo P-450 , Cães , Feminino , Humanos , Técnicas In Vitro , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Prostaglandin D(2) (PGD(2)) is derived from arachidonic acid and binds with high affinity to the G protein coupled receptors prostanoid DP(1) and DP(2). Interaction with DP(2) results in cell chemotaxis, eosinophil degranulation, eosinophil shape change, adhesion molecule upregulation and Th2 cytokine production. In allergic rhinitis and allergic asthma PGD(2) is released from mast cells in response to allergen challenge and may trigger symptoms such as sneezing, rhinorrhea, pruritus, mucus hypersecretion and pulmonary inflammation. In Japan, ramatroban, a dual prostanoid DP(2)/prostanoid TP receptor antagonist, is marketed for allergic rhinitis while selective DP(2) antagonists are currently under investigation as therapeutics for asthma and allergic rhinitis. In the studies described herein, we investigated the efficacy of AM156, a novel selective prostanoid DP(2) receptor antagonist, in murine models of allergic rhinitis and asthma. AM156 inhibited sneezing and nasal rubs in a model of allergic rhinitis. AM156 inhibited pulmonary inflammation and mucus hypersecretion induced by chronic inhalation of house dust mite. These results suggest that selective prostanoid DP(2) receptor antagonists such as AM156 may provide beneficial effects for the clinical treatment of diseases such as allergic rhinitis and asthma.
Assuntos
Antialérgicos/uso terapêutico , Asma/tratamento farmacológico , Benzilaminas/uso terapêutico , Pulmão/patologia , Pneumonia/tratamento farmacológico , Pyroglyphidae/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Animais , Antialérgicos/farmacologia , Benzilaminas/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Pulmão/imunologia , Metaplasia/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mucinas/metabolismo , Pneumonia/imunologia , Pneumonia/metabolismo , Rinite Alérgica Perene/metabolismoRESUMO
We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, a selective five-lipoxygenase-activating protein (FLAP) inhibitor, using rat and mouse models of acute inflammation. Oral administration of AM803 (1 mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12 h and an EC50 of approximately 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.12 mg/kg and 0.37 mg/kg, respectively. The inhibition measured 16 h following a single oral dose of 3 mg/kg was 86% and 41% for LTB4 and CysLTs, respectively. In an acute inflammation setting, AM803 dose-dependently reduced LTB4, CysLTs, plasma protein extravasation and neutrophil influx induced by peritoneal zymosan injection. Finally, AM803 increased survival time in mice exposed to a lethal intravenous injection of platelet activating factor (PAF). The magnitude of effect was similar to that of an inhibitor of five-lipoxygenase (5-LO) and LTA4 hydrolase but superior to a leukotriene CysLT1 receptor antagonist. In summary, AM803 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute inflammation and in a model of lethal shock.