RESUMEN
A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Receptores AMPA/metabolismo , Sulfonamidas/farmacología , Tiofenos/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Estabilidad de Medicamentos , Femenino , Humanos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Conformación Proteica , Ratas Sprague-Dawley , Esquizofrenia/tratamiento farmacológico , Relación Estructura-Actividad , Sulfonamidas/química , Tiofenos/química , Adulto JovenRESUMEN
Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.