RESUMEN
We discovered that the introduction of a methyl group to the benzylic position of the N-benzyl group in lead compound 1a has a dramatic effect on improving the binding selectivity of this ligand for the prostanoid receptors DP1 (receptor for prostaglandin D(2)) as compared to TP (receptor for thromboxane A(2)). Based on this discovery, we have synthesized a series of potent and highly selective DP1 antagonists. Among them, compound 1h was identified as a highly selective DP1 antagonist with excellent overall properties. It has a K(i) of 0.43 nM to DP1 in binding assay and an IC(50) of 2.5 nM in the DP1 functional assay. Its selectivity for DP1 over TP (the most potent receptor after DP1) exceeds 750-fold based on both binding and functional assays. These properties make 1h a very potent and highly selective DP1 receptor antagonist suitable for investigating the biological functions of DP1 in normal physiology and models of disease.
Asunto(s)
Carbazoles/química , Receptores de Prostaglandina/antagonistas & inhibidores , Sulfonas/química , Carbazoles/síntesis química , Carbazoles/farmacología , Humanos , Unión Proteica , Receptores de Prostaglandina/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
Azaindole based structures were evaluated as DP1 receptor antagonists. This work has lead to the discovery of potent, selective and distinct DP1 receptor antagonists.
Asunto(s)
Antagonistas de Prostaglandina/síntesis química , Receptores de Prostaglandina/antagonistas & inhibidores , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Antagonistas de Prostaglandina/farmacología , Receptores de Prostaglandina/fisiología , Relación Estructura-ActividadRESUMEN
A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).
Asunto(s)
Hidrógeno/química , Indoles/síntesis química , Indoles/farmacología , Piridinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Prostaglandina/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Humanos , Indoles/química , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
Asunto(s)
Indoles/síntesis química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Obstrucción de las Vías Aéreas/tratamiento farmacológico , Animales , Bilis/metabolismo , Unión Competitiva , Perros , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Indoles/farmacocinética , Indoles/farmacología , Macaca fascicularis , Masculino , Ratones , Microsomas/metabolismo , Descongestionantes Nasales/síntesis química , Descongestionantes Nasales/farmacocinética , Descongestionantes Nasales/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Ovinos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Ibudilast ophthalmic solution exhibited an improved clinical efficacy over cromoglycate in the treatment of allergic conjunctivitis. To further characterize its principal mode of action, the phosphodiesterase (PDE) inhibitory profile of ibudilast has been examined using human recombinant enzymes. Ibudilast, but not the other commonly used anti-allergic ophthalmic solutions including cromoglycate, ketotifen, tranilast and levocabastine, potently inhibits purified human PDE4A, 4B, 4C and 4D with IC50 values at 54, 65, 239 and 166 nM, respectively. Ibudilast effectively blocks lipopolysaccharide (LPS)-induced tumor necrosis factor (TNFalpha, IC50 = 6.2 microM) and N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene (LT) B4 biosynthesis (IC50 = 2.5 microM) in human whole blood, which are 3 and 6-fold more potent than cilomilast, respectively. The attenuated inflammatory and allergic responses from the potent and preferential PDE4 inhibition of ibudilast may have contributed significantly to its beneficial pharmacological responses and distinguishes ibudilast from the other ophthalmic solutions in the treatment of ocular allergy.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Soluciones Oftálmicas/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Piridinas/farmacología , Animales , Línea Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Perros , Relación Dosis-Respuesta a Droga , Humanos , Leucotrieno B4/biosíntesis , Leucotrieno B4/sangre , Lipopolisacáridos/farmacología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Proteínas Recombinantes , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.
Asunto(s)
Arginina/análogos & derivados , Compuestos de Bencidrilo/farmacología , Calcio/metabolismo , Proteínas de la Membrana/agonistas , Receptores de Complemento/agonistas , Animales , Arginina/farmacología , Unión Competitiva , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Células CHO , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Complemento C3a , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Ratas , Receptores de Complemento/antagonistas & inhibidores , Receptores de Complemento/genética , Transfección , Células U937 , beta-Lactamasas/genética , beta-Lactamasas/metabolismoRESUMEN
A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.
Asunto(s)
Indoles/química , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Indoles/síntesis química , Estructura Molecular , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Safrol/análogos & derivados , Safrol/química , Relación Estructura-ActividadRESUMEN
Two different series of very potent and selective EP(3) antagonists have been reported: a novel series of ortho-substituted cinnamic acids [Belley, M., Gallant, M., Roy, B., Houde, K., Lachance, N., Labelle, M., Trimble, L., Chauret, N., Li, C., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Greig, G. M., Slipetz, D., Metters, K. M., Gordon, R., Chan, C. C., Zamboni, R. J. Bioorg. Med. Chem. Lett.2005, 15, 527] and the acylsulfonamides of ortho-(arylmethyl)cinnamates. [(a) Juteau, H., Gareau, Y., Labelle, M., Sturino, C. F., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Metters, K. M. Bioorg. Med. Chem. 2001, 9, 1977; (b) Juteau, H., Gareau, Y., Labelle, M., Lamontagne, S., Tremblay, N., Carrière, M.-C., Denis, D., Sawyer, N., Metters, K. M. Bioorg. Med. Chem. Lett.2001, 11, 747] The structural differences between the two series, along with their biological activity in vivo, in vitro, and metabolism, are analyzed. Some of those compounds, including hybrids containing the best structural features of both series, possess K(i) as low as 0.6 nM on the EP(3) receptor.
Asunto(s)
Cinamatos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/farmacología , Cinamatos/química , Humanos , Sulfonamidas/químicaRESUMEN
The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor whose function in vivo has been incompletely characterized. One of the reasons is that its current known ligands, prostaglandin D(2) and some of its metabolites, have either poor selectivity for CRTH2 or are metabolically unstable in vivo. In this study, we describe the biological and pharmacological properties of L-888,607, the first synthetic potent and selective CRTH2 agonist. We show that L-888,607 exhibits 1) subnanomolar affinity for the human CRTH2 receptor, 2) high selectivity over all other prostanoid receptors and other receptors tested, 3) agonistic activity on recombinant and endogenously expressed CRTH2 receptor, and 4) relative stability in vivo. L-888,607 thus represents a suitable tool to investigate the in vivo function of CRTH2.
Asunto(s)
Acetatos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Receptores Inmunológicos/agonistas , Receptores de Prostaglandina/agonistas , Acetatos/química , Acetatos/metabolismo , Animales , Quimiotaxis de Leucocito/efectos de los fármacos , Quimiotaxis de Leucocito/fisiología , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Eosinófilos/fisiología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Humanos , Indometacina/análogos & derivados , Indometacina/farmacología , Ligandos , Masculino , Ratones , Ratones Endogámicos ICR , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMEN
The synthesis and the EP(1) receptor binding affinity of 2,3-diarylthiophene derivatives are described. The evaluation of the structure-activity relationship (SAR) in this series led to the identification of compounds 4, 7, and 12a, which exhibit high affinity for the human EP(1) receptor and a selectivity greater than 100-fold against the EP(2), EP(3), EP(4), DP, FP, and IP receptors and greater than 25-fold versus the TP receptor. These three antagonists present good pharmacokinetics in rats and significant differences in the way they are distributed in the brain.
Asunto(s)
Receptores de Prostaglandina E/antagonistas & inhibidores , Tiofenos/síntesis química , Tiofenos/farmacocinética , Animales , Encéfalo/metabolismo , Línea Celular , Semivida , Humanos , Farmacocinética , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Tiofenos/farmacología , Distribución TisularRESUMEN
A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.
Asunto(s)
Cinamatos/síntesis química , Cinamatos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Línea Celular , Cinamatos/metabolismo , AMP Cíclico/biosíntesis , Humanos , Farmacocinética , Unión Proteica , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP3 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
A series of 2-substituted N-benzyl benzimidazole containing molecules has been synthesized and its structure-activity relationship for the human DP receptor has been evaluated. Selective DP antagonists with nanomolar potency for the DP receptor were identified in this novel series of benzimidazoles.
Asunto(s)
Antialérgicos/química , Bencimidazoles/química , Receptores de Prostaglandina/antagonistas & inhibidores , Rinitis Alérgica Perenne/tratamiento farmacológico , Antialérgicos/metabolismo , Antialérgicos/uso terapéutico , Bencimidazoles/metabolismo , Bencimidazoles/uso terapéutico , Unión Competitiva/efectos de los fármacos , Humanos , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante , Receptores Inmunológicos , Receptores de Prostaglandina/metabolismo , Rinitis Alérgica Perenne/metabolismoRESUMEN
Analogues of PGE(2) wherein the hydroxycyclopentanone ring has been replaced by a lactam have been prepared and evaluated as ligands for the EP(4) receptor. An optimized compound (19a) shows high potency and agonist efficacy at the EP(4) receptor and is highly selective over the other seven known prostaglandin receptors.
Asunto(s)
Dinoprostona/análogos & derivados , Dinoprostona/farmacología , Pirrolidinonas/farmacología , Receptores de Prostaglandina E/agonistas , Tetrazoles/farmacología , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Dinoprostona/síntesis química , Diseño de Fármacos , Semivida , Humanos , Indicadores y Reactivos , Pirrolidinonas/síntesis química , Subtipo EP4 de Receptores de Prostaglandina E , Tetrazoles/síntesis químicaRESUMEN
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.