RESUMEN
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hígado/efectos de los fármacos , Pirrolidinas/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células Hep G2 , Humanos , Hígado/enzimología , Hígado/metabolismo , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Estearoil-CoA Desaturasa/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Hígado/enzimología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Acetatos/farmacología , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hidrólisis , Concentración 50 Inhibidora , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Obesidad/tratamiento farmacológico , Estearoil-CoA Desaturasa/química , Relación Estructura-Actividad , Tetrazoles/farmacologíaRESUMEN
The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.
Asunto(s)
Acetatos/síntesis química , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Hígado/enzimología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tetrazoles/síntesis química , Acetatos/química , Acetatos/farmacología , Animales , Línea Celular , Difusión , Perros , Femenino , Glándula de Harder/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacología , Técnicas In Vitro , Transportador 1 de Anión Orgánico Específico del Hígado , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ratas , Ratas Sprague-Dawley , Piel/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Especificidad de la Especie , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacología , Distribución TisularRESUMEN
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
Some DP1 receptor antagonists from an indole-containing series were shown to cause in vitro covalent binding to protein in rat and human liver microsomes. Glutathione trapping experiments along with in vitro labeling assays confirmed that the presence of a strong electron withdrawing group was necessary to abrogate in vitro covalent binding, leading to the discovery of MK-0524. Hepatocyte incubations and in vivo studies showed that acyl-glucuronide formation did not translate into covalent binding.
Asunto(s)
Glutatión/metabolismo , Indoles/agonistas , Indoles/metabolismo , Microsomas Hepáticos/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Electrones , Glucurónidos/biosíntesis , Hepatocitos/metabolismo , Hepatocitos/ultraestructura , Humanos , Indoles/química , Proteínas/metabolismo , RatasRESUMEN
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
Metabolites of the potent DP antagonist, MK-0524, were generated using in vitro systems including hepatic microsomes and hepatocytes. Four metabolites (two hydroxylated diastereomers, a ketone and an acyl glucuronide) were characterized by LC-MS/MS and 1H NMR. Larger quantities of these metabolites were prepared by either organic synthesis or biosynthetically to be used as standards in other studies. The propensity for covalent binding was assessed and was found to be acceptable (<50 pmol-equiv/mg protein).
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Prostaglandina D2/antagonistas & inhibidores , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Perros , Humanos , Macaca mulatta , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Microsomas Hepáticos/metabolismo , Oxidación-Reducción , Conejos , Ratas , Saimiri , Ovinos , Espectrofotometría UltravioletaRESUMEN
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
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
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.