RESUMEN
A novel class of human ß(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ß(3)-AR agonists. As observed, many of the ß(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ß(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional ß(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new ß(3)-AR agonists containing the pyrrolidine moiety.
Asunto(s)
Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacología , Pirrolidinas/química , Receptores Adrenérgicos beta 3/efectos de los fármacos , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Modelos MolecularesRESUMEN
We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.
Asunto(s)
Acetatos/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Flúor/química , Piperidinas/química , Acetatos/síntesis química , Acetatos/farmacocinética , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Compuestos de Diazonio/química , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacocinética , Ratas , Receptores Notch/metabolismoRESUMEN
Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARgamma agonists. Synthetic modifications of these leads led to a series of potent substituted 3-benzyl-2-methyl indoles, a subset of which were noted to be selective PPARgamma modulators (SPPARgammaMs). SPPARgammaM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARgamma full agonist in a rodent efficacy model.
Asunto(s)
Mediadores de Inflamación/metabolismo , PPAR gamma/agonistas , Animales , Benzoatos/síntesis química , Benzoatos/farmacología , Benzoatos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Indoles/síntesis química , Indoles/farmacología , Indoles/uso terapéutico , Ligandos , Estructura Molecular , PPAR gamma/metabolismoRESUMEN
A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.