RESUMEN
Disturbance of the dynamic balance between tyrosine phosphorylation and dephosphorylation of signaling molecules, controlled by protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is known to lead to the development of cancer. While most approved targeted cancer therapies are tyrosine kinase inhibitors, PTPs have long been stigmatized as undruggable and have only recently gained renewed attention in drug discovery. One PTP target is the Src-homology 2 domain-containing phosphatase 2 (SHP2). SHP2 is implicated in tumor initiation, progression, metastasis, and treatment resistance, primarily because of its role as a signaling nexus of the extracellular signal-regulated kinase pathway, acting upstream of the small GTPase Ras. Efforts to develop small molecules that target SHP2 are ongoing, and several SHP2 allosteric inhibitors are currently in clinical trials for the treatment of solid tumors. However, while the reported allosteric inhibitors are highly effective against cells expressing WT SHP2, none have significant activity against the most frequent oncogenic SHP2 variants that drive leukemogenesis in several juvenile and acute leukemias. Here, we report the discovery of novel furanylbenzamide molecules as inhibitors of both WT and oncogenic SHP2. Importantly, these inhibitors readily cross cell membranes, bind and inhibit SHP2 under physiological conditions, and effectively decrease the growth of cancer cells, including triple-negative breast cancer cells, acute myeloid leukemia cells expressing either WT or oncogenic SHP2, and patient-derived acute myeloid leukemia cells. These novel compounds are effective chemical probes of active SHP2 and may serve as starting points for therapeutics targeting WT or mutant SHP2 in cancer.
Asunto(s)
Benzamidas , Inhibidores Enzimáticos , Leucemia Mieloide Aguda , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Benzamidas/farmacología , Carcinogénesis , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/enzimología , Oncogenes , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismoRESUMEN
LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which has progressed into healthy volunteer Phase 1 trials, making it the "first-in-class" small-molecule LOXL2 inhibitor to enter clinical development.
Asunto(s)
Aminoácido Oxidorreductasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Piridinas/química , Piridinas/farmacología , Administración Oral , Aminoácido Oxidorreductasas/metabolismo , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Fibrosis , Halogenación , Humanos , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/patología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/patología , Masculino , Metilación , Ratones Endogámicos C57BL , Modelos Moleculares , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and three other amine oxidases (MAO-A, MAO-B, and SSAO). Compound 20 is the first published small molecule inhibitor selective for LOXL2 over LOX.
RESUMEN
Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/enzimología , Hidrolasas Diéster Fosfóricas/metabolismo , Piperazinas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Piperazinas/farmacocinética , Piperazinas/uso terapéuticoRESUMEN
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/metabolismo , Animales , Línea Celular Tumoral , Cristalización , Células HEK293 , Humanos , Ratones , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
AIM: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. METHOD: Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. RESULTS: There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nM and 89 nM in the Western European and Japanese studies, respectively. CONCLUSION: GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa , Indoles , Leucotrieno E4/sangre , Ácidos Pentanoicos , Inhibidores de Proteína Activante de 5-Lipoxigenasa/efectos adversos , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Pueblo Asiatico , Biomarcadores/sangre , Biomarcadores/orina , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Leucotrieno B4/sangre , Leucotrieno B4/orina , Leucotrieno E4/orina , Masculino , Persona de Mediana Edad , Ácidos Pentanoicos/efectos adversos , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Población Blanca , Adulto JovenRESUMEN
BACKGROUND: Allergic conjunctivitis is characterized by itchy, watery and swollen eyes which occur in response to exposure to seasonal or environmental allergens. The early phase reaction of allergic conjunctivitis is primarily mediated by mast cell degranulation while the late phase reaction is driven by Th2 cells and eosinophils. Prostaglandin D(2) (PGD(2)), released from mast cells, is present in allergic conjunctival tears and may elicit classical allergic responses via interaction with the high-affinity DP2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells, CRTh2). Furthermore, antagonism of this receptor is well known to inhibit eosinophil chemotaxis, basophil activation and Th2 cytokine production. PGD(2), therefore, may be involved in both early and late phase reactions in response to allergen challenge. METHODS: Thus, we explored whether our novel and selective DP2 antagonist AM156 would be efficacious in animal models of allergic conjunctivitis. Furthermore, as respiratory syncytial virus (RSV) has been implicated in the pathogenesis of allergic conjunctivitis, we examined the effects of DP2 antagonism in a murine model of RSV ocular infection. RESULTS: Utilizing a guinea pig ovalbumin model and a murine ragweed model we demonstrated that AM156 reduces redness, discharge and swelling in response to allergen challenge. These effects were equal to or greater than those of current clinical treatment options for allergic conjunctivitis including topical corticosteroids and a dual-mechanism antihistamine and decongestant. AM156 significantly reduced RSV-induced ocular inflammation and IL-4 production. CONCLUSION: These results suggest that a topical DP2 antagonist such as AM156 may represent a novel therapeutic for allergic conjunctivitis.
Asunto(s)
Antialérgicos/uso terapéutico , Bencilaminas/uso terapéutico , Conjuntivitis Alérgica/tratamiento farmacológico , Conjuntivitis Viral/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Administración Tópica , Alérgenos/inmunología , Ambrosia/inmunología , Animales , Conjuntivitis Alérgica/inmunología , Conjuntivitis Alérgica/metabolismo , Conjuntivitis Viral/inmunología , Conjuntivitis Viral/metabolismo , Modelos Animales de Enfermedad , Femenino , Cobayas , Interleucina-4/inmunología , Interleucina-4/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Receptores Inmunológicos/inmunología , Receptores de Prostaglandina/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/metabolismoRESUMEN
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.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Antiasmáticos/síntesis química , Indoles/síntesis química , Ácidos Pentanoicos/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Administración Oral , Animales , Antiasmáticos/farmacocinética , Antiasmáticos/farmacología , Lavado Broncoalveolar , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Femenino , Humanos , Técnicas In Vitro , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Modelos Animales de Enfermedad , Descubrimiento de Drogas , Fenilacetatos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Rinitis Alérgica Perenne/tratamiento farmacológico , Animales , Disponibilidad Biológica , Perros , Ratones , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/uso terapéutico , RatasRESUMEN
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.
Asunto(s)
Modelos Animales de Enfermedad , Compuestos de Metilurea/uso terapéutico , Fenilacetatos/uso terapéutico , Antagonistas de Prostaglandina/uso terapéutico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Rinitis Alérgica Perenne/tratamiento farmacológico , Adulto , Animales , Perros , Femenino , Cobayas , Células HEK293 , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Masculino , Compuestos de Metilurea/química , Compuestos de Metilurea/farmacología , Ratones , Ratones Endogámicos BALB C , Fenilacetatos/química , Fenilacetatos/farmacología , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Neumonía/metabolismo , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacología , Unión Proteica/fisiología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/inmunología , Receptores de Prostaglandina/metabolismo , Rinitis Alérgica Perenne/inmunología , Rinitis Alérgica Perenne/metabolismoRESUMEN
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.
Asunto(s)
Fenilacetatos/química , Piridinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Modelos Animales de Enfermedad , Perros , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Humanos , Inflamación/tratamiento farmacológico , Ratones , Fenilacetatos/farmacocinética , Fenilacetatos/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMEN
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.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Indoles/farmacología , Inflamación/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Ácidos Pentanoicos/farmacología , Propionatos/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa , Animales , Enfermedad Crónica , Cisteína/biosíntesis , Modelos Animales de Enfermedad , Femenino , Humanos , Indoles/farmacocinética , Indoles/uso terapéutico , Inflamación/tratamiento farmacológico , Leucotrieno B4/biosíntesis , Leucotrienos/biosíntesis , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Ratones , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/uso terapéutico , Factor de Activación Plaquetaria/farmacología , Propionatos/farmacocinética , Propionatos/uso terapéutico , Ratas , Especificidad por Sustrato , Zimosan/farmacologíaRESUMEN
AM643 (compound 6, 3-{3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid) was identified as a potential candidate for formulation as a topical agent for the treatment of skin disorders involving leukotriene production. Dermal application of 6 using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling.
Asunto(s)
Inhibidores Enzimáticos/química , Indoles/síntesis química , Propionatos/síntesis química , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Administración Tópica , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Indoles/química , Indoles/uso terapéutico , Leucotrienos/biosíntesis , Ratones , Propionatos/química , Propionatos/uso terapéutico , Ratas , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Antialérgicos/uso terapéutico , Asma/tratamiento farmacológico , Bencilaminas/uso terapéutico , Pulmón/patología , Neumonía/tratamiento farmacológico , Pyroglyphidae/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Rinitis Alérgica Perenne/tratamiento farmacológico , Animales , Antialérgicos/farmacología , Bencilaminas/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina E/sangre , Pulmón/inmunología , Metaplasia/inmunología , Ratones , Ratones Endogámicos BALB C , Mucinas/metabolismo , Neumonía/inmunología , Neumonía/metabolismo , Rinitis Alérgica Perenne/metabolismoRESUMEN
Three US applications describing a narrow, closely related series of antagonists of the action of leukotriene B(4) on the BLT1 and BLT2 receptors are described. The generic structure claimed is a lipophilic linked diphenyl core containing two acid groups appended to the central phenyl ring. The terminal phenyl moiety contains disubstitution at the 3'- and 5'-positions. These three applications differ in the nature of the substituent on the terminal phenyl group as well as the linking moiety between the two phenyl rings. These compounds are claimed to have utility in inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease.
Asunto(s)
Antagonistas de Leucotrieno/farmacología , Leucotrieno B4/antagonistas & inhibidores , Receptores de Leucotrieno B4/antagonistas & inhibidores , Animales , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Antagonistas de Leucotrieno/química , Patentes como AsuntoRESUMEN
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.
Asunto(s)
Pulmón/efectos de los fármacos , Moco/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/prevención & control , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Mucosa Respiratoria/efectos de los fármacos , Fumar/efectos adversos , Animales , Bencilaminas/farmacocinética , Bencilaminas/farmacología , Línea Celular , Movimiento Celular , Femenino , Cobayas , Humanos , Técnicas In Vitro , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Pulmón/inmunología , Pulmón/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Metaplasia , Ratones , Ratones Endogámicos BALB C , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Niacina/análogos & derivados , Niacina/farmacocinética , Niacina/farmacología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/patologíaRESUMEN
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.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Indoles/química , Inhibidores de la Lipooxigenasa/química , Proteínas de la Membrana/antagonistas & inhibidores , Ácidos Pentanoicos/química , Proteínas Activadoras de la 5-Lipooxigenasa , Animales , Proteínas Portadoras/metabolismo , Humanos , Indoles/síntesis química , Indoles/farmacología , Leucotrienos/sangre , Leucotrienos/metabolismo , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Proteínas de la Membrana/metabolismo , Ratones , Modelos Animales , Ácidos Pentanoicos/síntesis química , Ácidos Pentanoicos/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Oftalmopatías/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Inflamación/patología , Inflamación/prevención & control , Proteínas de la Membrana/antagonistas & inhibidores , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Proteínas Activadoras de la 5-Lipooxigenasa , Animales , Ojo/virología , Oftalmopatías/inmunología , Oftalmopatías/patología , Femenino , Interleucina-4/biosíntesis , Pulmón/virología , Ratones , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/patología , Virus Sincitiales Respiratorios/inmunología , Carga ViralRESUMEN
The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 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 (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.