RESUMEN
Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimer's disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable "druggable" pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a ~100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.
RESUMEN
The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inflamación/tratamiento farmacológico , Microsomas Hepáticos/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirazoles/farmacología , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/química , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Inflamación/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Osteoartritis/metabolismo , Dolor/metabolismo , Pirazoles/administración & dosificación , Pirazoles/química , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
Asunto(s)
Glucemia/efectos de los fármacos , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacología , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas ZuckerRESUMEN
Potent 5-HT(2A) inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation.
Asunto(s)
Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Urea/análogos & derivados , Urea/farmacología , Humanos , Agregación Plaquetaria/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Relación Estructura-ActividadRESUMEN
GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.