RESUMEN
Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLEâ¯=â¯0.3, ΔFsp3â¯=â¯0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Receptores de Superficie Celular/agonistas , Tiazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/metabolismo , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
Treatment of various ketones with ethyl dibromofluoroacetate in the presence of diethylzinc and dimethylaminoethanol or triphenylphosphine provides rapid access to corresponding fluorinated glycidic esters. Simplified workup allowed first characterization of these compounds.
Asunto(s)
Compuestos Epoxi/síntesis química , Hidrocarburos Fluorados/síntesis química , Cetonas/química , Catálisis , Química Orgánica/métodos , Compuestos Epoxi/química , Ésteres , Hidrocarburos Fluorados/química , Estructura Molecular , EstereoisomerismoRESUMEN
The rhodium-catalyzed 1,4-addition of arylboronic acids to an enantiopure heterocyclic acceptor proceeds under ligand control to effect an asymmetric synthesis of functionalized pyrrolizidinones. The protocol allows convenient access to all four stereoisomers of pyrrolizidinone 3a (Ar = Ph) by appropriate selection of substrate and catalyst.
RESUMEN
The enantioselective synthesis of a potent Maxi-K potassium channel opener (BMS-204352) mediated by N-fluoroammonium salts of cinchona alkaloids is described. Two synthetic pathways were evaluated. An ee as high as 88% was achieved (>99% after a single recrystallisation).