RESUMO
The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor that has been reported to modulate inflammatory responses in various rodent models of asthma, allergic rhinitis and atopic dermatitis. In this study, we describe the biological and pharmacological properties of {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetic acid (MK-7246), a novel synthetic CRTH2 antagonist. We show that MK-7246 1) has high affinity for the human, monkey, dog, rat, and mouse CRTH2, 2) interacts with CRTH2 in a reversible manner, 3) exhibits high selectivity over all prostanoid receptors as well as 157 other receptors and enzymes, 4) acts as a full antagonist on recombinant and endogenously expressed CRTH2, 5) demonstrates good oral bioavailability and metabolic stability in various animal species, 6) yields ex vivo blockade of CRTH2 on eosinophils in monkeys and sheep, and 7) significantly blocks antigen-induced late-phase bronchoconstriction and airway hyper-responsiveness in sheep. MK-7246 represents a potent and selective tool to further investigate the in vivo function of CRTH2.
Assuntos
Carbolinas/química , Carbolinas/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/biossíntese , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/biossíntese , Células Th2/metabolismo , Animais , Cães , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Células HEK293 , Humanos , Macaca fascicularis , Camundongos , Inibidores da Agregação Plaquetária/farmacologia , Ligação Proteica/imunologia , Ratos , Receptores Imunológicos/metabolismo , Receptores Imunológicos/fisiologia , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/fisiologia , Ovinos , Especificidade da Espécie , Células Th2/efeitos dos fármacosRESUMO
We disclose herein our preliminary SAR study on the identification of substituted benzothiophene derivatives as PGE(2) subtype 4 receptor antagonists. A potent EP(4) antagonist 6a (K(i)=1.4nM with 10% HSA) was identified. Furthermore, we found that an acidic group was not essential for the EP(4) antagonizing activity in the series and neutral replacements were identified. This opens a new direction for future EP(4) antagonist design.
Assuntos
Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Tiofenos/química , Tiofenos/farmacologia , Linhagem Celular , Humanos , Ligação Proteica , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.
Assuntos
Indóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/farmacocinética , Indóis/uso terapêutico , Ligantes , Ratos , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-AtividadeRESUMO
Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.
Assuntos
Amidas/química , Indóis/química , Naftalenos/química , Quinolinas/química , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Compostos de Sulfonilureia/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/síntese química , Indóis/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacocinéticaRESUMO
In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.
Assuntos
Carbolinas/química , Pneumopatias/tratamento farmacológico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Carbolinas/farmacocinética , Carbolinas/uso terapêutico , Humanos , Macaca mulatta , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Carbazóis/química , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonas/química , Carbazóis/síntese química , Carbazóis/farmacologia , Humanos , Ligação Proteica , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologiaRESUMO
The discovery of a highly potent and selective EP(4) antagonist MF-766 is discussed. This N-benzyl indole derivative exhibits good pharmacokinetic profile and unprecedented in vivo potency in the rat AIA model.
Assuntos
Benzoatos/farmacologia , Indóis/farmacologia , Dor/tratamento farmacológico , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Artrite/tratamento farmacológico , Benzoatos/química , Benzoatos/uso terapêutico , Células Cultivadas , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Hepatócitos , Humanos , Indóis/química , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-AtividadeRESUMO
Azaindole based structures were evaluated as DP1 receptor antagonists. This work has lead to the discovery of potent, selective and distinct DP1 receptor antagonists.
Assuntos
Antagonistas de Prostaglandina/síntese química , Receptores de Prostaglandina/antagonistas & inibidores , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Antagonistas de Prostaglandina/farmacologia , Receptores de Prostaglandina/fisiologia , Relação Estrutura-AtividadeRESUMO
Previous evidence has implicated E prostanoid receptor 4 (EP4) in mechanical hyperalgesia induced by subplantar inflammation. However, its role in chronic arthritis remains to be further defined because previous attempts have generated two conflicting lines of evidence, with one showing a marked reduction of arthritis induced by a collagen antibody in mice lacking EP4, but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen. Here, we assessed the effect of a novel and selective EP4 antagonist MF498 [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide] on inflammation in adjuvant-induced arthritis (AIA), a rat model for rheumatoid arthritis (RA), and joint pain in a guinea pig model of iodoacetate-induced osteoarthritis (OA). In the AIA model, MF498, but not the antagonist for EP1, MF266-1 [1-(5-{3-[2-(benzyloxy)-5-chlorophenyl]-2-thienyl}pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol] or EP3 MF266-3 [(2E)-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide], inhibited inflammation, with a similar efficacy as a selective cyclooxygenase 2 (COX-2) inhibitor MF-tricyclic. In addition, MF498 was as effective as an nonsteroidal anti-inflammatory drug, diclofenac, or a selective microsomal prostaglandin E synthase-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile], in relieving OA-like pain in guinea pigs. When tested in rat models of gastrointestinal toxicity, the EP4 antagonist was well tolerated, causing no mucosal leakage or erosions. Lastly, we evaluated the renal effect of MF498 in a furosemide-induced diuresis model and demonstrated that the compound displayed a similar renal effect as MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], reducing furosemide-induced natriuresis by approximately 50%. These results not only suggest that EP4 is the major EP receptor in both RA and OA but also provide a proof of principle to the concept that antagonism of EP4 may be useful for treatment of arthritis.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Quinolinas/uso terapêutico , Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/genética , Furosemida/farmacologia , Cobaias , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Natriurese/efeitos dos fármacos , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E Subtipo EP4RESUMO
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).
Assuntos
Hidrogênio/química , Indóis/síntese química , Indóis/farmacologia , Piridinas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Humanos , Indóis/química , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.
Assuntos
Artrite Experimental/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Cães , Cobaias , Humanos , Macaca mulatta , Estrutura Molecular , Quinolinas/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-Atividade , Sulfonamidas/farmacocinéticaRESUMO
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.
Assuntos
Indóis/síntese química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Obstrução das Vias Respiratórias/tratamento farmacológico , Animais , Bile/metabolismo , Ligação Competitiva , Cães , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Indóis/farmacocinética , Indóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Microssomos/metabolismo , Descongestionantes Nasais/síntese química , Descongestionantes Nasais/farmacocinética , Descongestionantes Nasais/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ovinos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.
Assuntos
Analgésicos/síntese química , Benzoatos/síntese química , Ciclopropanos/síntese química , Antagonistas de Prostaglandina/síntese química , Receptores de Prostaglandina E/metabolismo , Tiofenos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzoatos/química , Benzoatos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Dor/tratamento farmacológico , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacocinéticaRESUMO
Prostaglandin E(2) (PGE(2)) is a major mediator of inflammation and is present at high concentrations in the synovial fluid of rheumatoid arthritis (RA) patients. PGE(2), acting through the EP4 receptor, has both pro- and anti-inflammatory roles in vivo. To shed light on this dual role of PGE(2), we investigated its effects in whole blood and in primary human fibroblast-like synoviocytes (FLS). Gene expression analysis in human leukocytes, confirmed at the protein level, revealed an EP4-dependent inhibition of the expression of genes involved in the IFN-gamma-activation pathway, including IFN-gamma itself. This effect of the PGE(2)/EP4 axis on IFN-gamma is a reciprocal phenomenon since IFN-gamma blocks PGE(2) release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-gamma and PGE(2) extends to downstream cytokine and chemokine release; PGE(2) counters the effects of IFN-gamma, on the release of IP-10, IL-8, TNF-alpha and IL-1beta. To gain further insight into IFN-gamma-mediated cellular events in RA, we assessed the effects of IFN-gamma on gene expression in FLS. We observed an IFN-gamma-dependent up-regulation of macrophage-attracting chemokines, and down-regulation of metalloprotease expression. These results suggest the existence of a mutually antagonistic relationship between PGE(2) and IFN-gamma, which may represent a fundamental mechanism of immune control in diseases such as RA.
Assuntos
Artrite Reumatoide/imunologia , Citocinas/metabolismo , Dinoprostona/metabolismo , Interferon gama/metabolismo , Receptores de Prostaglandina E/metabolismo , Artrite Reumatoide/metabolismo , Citocinas/imunologia , Dinoprostona/sangue , Regulação para Baixo , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Interferon gama/genética , Interferon gama/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Prostaglandina E/imunologia , Receptores de Prostaglandina E Subtipo EP4 , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Regulação para CimaRESUMO
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.
Assuntos
Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Indóis/síntese química , Estrutura Molecular , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Safrol/análogos & derivados , Safrol/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Cinamatos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/farmacologia , Cinamatos/química , Humanos , Sulfonamidas/químicaRESUMO
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.
Assuntos
Acetatos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores Imunológicos/agonistas , Receptores de Prostaglandina/agonistas , Acetatos/química , Acetatos/metabolismo , Animais , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/fisiologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Eosinófilos/fisiologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Humanos , Indometacina/análogos & derivados , Indometacina/farmacologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
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.
Assuntos
Receptores de Prostaglandina E/antagonistas & inibidores , Tiofenos/síntese química , Tiofenos/farmacocinética , Animais , Encéfalo/metabolismo , Linhagem Celular , Meia-Vida , Humanos , Farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-Atividade , Tiofenos/farmacologia , Distribuição TecidualRESUMO
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.
Assuntos
Cinamatos/síntese química , Cinamatos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Linhagem Celular , Cinamatos/metabolismo , AMP Cíclico/biossíntese , Humanos , Farmacocinética , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP3 , Relação Estrutura-AtividadeRESUMO
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.