RESUMEN
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
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
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
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
BACKGROUND: Prostaglandin D2 (PGD2) is released from mast cells during the allergic response. OBJECTIVE: Since PGD2 has been shown to induce nasal congestion in humans, we investigated the distribution of hematopoietic prostaglandin D synthase (PGDS) and the two PGD2 receptors, DP and CRTH2 in human nasal mucosa from healthy subjects and subjects suffering from polyposis, a severe form of chronic rhinosinusitis. METHODS: DP mRNA expression was detected by in situ hybridization while PGDS, CRTH2 and various leukocyte markers expression were revealed by immunohistochemistry. RESULTS: In the normal mucosa, PGDS was only detected in few resident mast cells while CRTH2 was undetectable. In contrast, DP receptor mRNA was detected in epithelial goblet cells, serous glands and in the vasculature. In the nasal mucosa of subjects suffering from polyposis: (1) PGDS was detected in mast cells and other large infiltrating inflammatory cells, (2) both DP mRNA and CRTH2 were detected in eosinophils and (3) CRTH2 was detected on a subset of infiltrating T cells. Although DP mRNA could not be detected in the T cells invading the nasal mucosa, it was found to be expressed in the T cells present in the lymph node and the thymus from normal individuals. CONCLUSION: This study indicates that cells capable of producing PGD2 are present in the nasal mucosa and that both PGD2 receptors, DP and CRTH2, might play a role in inflammatory disease of the upper airways.
Asunto(s)
Oxidorreductasas Intramoleculares/biosíntesis , Mastocitos/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasales/metabolismo , Receptores Inmunológicos/biosíntesis , Receptores de Prostaglandina/biosíntesis , Adulto , Anciano , Eosinófilos/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Hibridación in Situ , Inflamación/metabolismo , Inflamación/patología , Lipocalinas , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Nasal/citología , Mucosa Nasal/patología , Pólipos Nasales/patología , ARN Mensajero/biosíntesis , Linfocitos T/metabolismo , Timo/citología , Timo/metabolismoRESUMEN
Potent and selective ligands for the human EP3 prostanoid receptor are described. Triaryl compounds bearing an ortho-substituted propionic acid moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinities of key compound on all eight human prostanoid receptors is reported.
Asunto(s)
Receptores de Prostaglandina E/efectos de los fármacos , Animales , Línea Celular Tumoral , AMP Cíclico/metabolismo , Humanos , Indicadores y Reactivos , Cinética , Conformación Proteica , Ratas , Subtipo EP3 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
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
1. The recombinant human prostaglandin D(2) (PGD(2)) receptor, hCRTH2, has been expressed in HEK293(EBNA) and characterized with respect to radioligand binding and signal transduction properties. High and low affinity binding sites for PGD(2) were identified in the CRTH2 receptor population by saturation analysis with respective equilibrium dissociation constants (K(D)) of 2.5 and 109 nM. This revealed that the affinity of PGD(2) for CRTH2 is eight times less than its affinity for the DP receptor. 2. Equilibrium competition binding assays revealed that of the compounds tested, only PGD(2) and several related metabolites bound with high affinity to CRTH2 (K(i) values ranging from 2.4 to 34.0 nM) with the following rank order of potency: PGD(2)>13,14-dihydro-15-keto PGD(2)>15-deoxy-Delta(12,14)-PGJ(2)>PGJ(2)>Delta(12)-PGJ(2)>15(S)-15 methyl-PGD(2). This is in sharp contrast with the rank order of potency obtained at DP : PGD(2)>PGJ(2)>Delta(12)-PGJ(2)>15-deoxy-Delta(12,14)-PGJ(2) >>>13,14-dihydro-15-keto-PGD(2). 3. Functional studies demonstrated that PGD(2) activation of recombinant CRTH2 results in decrease of intracellular cAMP in a pertussis toxin-sensitive manner. Therefore, we showed that CRTH2 can functionally couple to the G-protein G(alphai/o). PGD(2) and related metabolites were tested and their rank order of potency followed the results of the membrane binding assay. 4. By Northern blot analysis, we showed that, besides haemopoietic cells, CRTH2 is expressed in many other tissues such as brain, heart, thymus, spleen and various tissues of the digestive system. In addition, in situ hybridization studies revealed that CRTH2 mRNA is expressed in human eosinophils. Finally, radioligand binding studies demonstrated that two eosinophilic cell lines, butyric acid-differentiated HL-60 and AML 14.3D10, also endogenously express CRTH2.