RESUMEN
GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.
Asunto(s)
Receptores Acoplados a Proteínas G/agonistas , Urea/análogos & derivados , Amidas/química , Amidas/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Conformación Molecular , Unión Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/metabolismo , Relación Estructura-Actividad , Urea/metabolismoRESUMEN
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.
Asunto(s)
Isoindoles/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Isoindoles/síntesis química , Isoindoles/química , Ratones , Modelos Animales , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Relación Estructura-ActividadRESUMEN
A number of FLAP inhibitors have been progressed to clinical trials for respiratory and other inflammatory indications but so far no drug has reached the market. With this Digest we assess the opportunity to develop FLAP inhibitors for indications beyond respiratory disease, and in particular for atherosclerotic cardiovascular disease. We also show how recently disclosed FLAP inhibitors have structurally evolved from the first generation FLAP inhibitors paving the way for new compound classes.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Animales , Asma/tratamiento farmacológico , Aterosclerosis/tratamiento farmacológico , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Inflamación/tratamiento farmacológico , Leucotrienos/metabolismo , Estructura MolecularRESUMEN
A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.
Asunto(s)
Canal de Potasio Kv1.5/antagonistas & inhibidores , Lactamas/química , Bloqueadores de los Canales de Potasio/química , Pirrolidinonas/química , Sulfonamidas/química , Animales , Perros , Semivida , Humanos , Canal de Potasio Kv1.5/metabolismo , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacocinética , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Conejos , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naÑve, p<0.01) in plasma triacylglycerol (TAG) concentration.
Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Aciltransferasas/metabolismo , Administración Oral , Animales , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Humanos , Ratones , Nanoestructuras/química , Povidona/química , Relación Estructura-Actividad , Triglicéridos/metabolismoRESUMEN
GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.
Asunto(s)
Hipoglucemiantes/química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Obesidad/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Acetil-CoA Carboxilasa/metabolismo , Animales , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/enzimología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Ácidos Grasos/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Malonil Coenzima A/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Obesidad/enzimología , Ratas , Ratas Zucker , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-ActividadRESUMEN
A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure-activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)-pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog. AZD6642 shows high specific potency and low lipophilicity, resulting in a selective and metabolically stable profile. On the basis of initial PK/PD relation measured, a low dose to human was predicted.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Antiinflamatorios/síntesis química , Ácidos Picolínicos/síntesis química , Pirazinas/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Animales , Antiinflamatorios/farmacología , Perros , Descubrimiento de Drogas , Humanos , Ácidos Picolínicos/farmacología , Ácidos Picolínicos/toxicidad , Pirazinas/farmacología , Pirazinas/toxicidad , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Structure 1 is the major component obtained by the reaction of two equivalents of RLi and one equivalent of CuCN; other proposed structures can now be ruled out on the basis of 15 N NMR spectroscopic and theoretical studies. Thus, these useful synthetic reagents should be considered as cyano-Gilman reagents R2 CuLiâ LiCN and not "higher order cyanocuprates" R2 Cu(CN)Li2 .
RESUMEN
G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.