RESUMEN
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Indoles/síntesis química , Diseño de Fármacos , Humanos , Relación Estructura-ActividadRESUMEN
A new approach to the synthesis of pyrimidines and cyclopentenones is described. The method exploits the reactivity of alpha,beta-unsaturated acetals with aromatic nitriles in the presence of the Schlosser's superbase LIC-KOR.
Asunto(s)
Acetales/química , Butanos/química , Ciclopentanos/síntesis química , Éteres de Etila/química , Iminas/síntesis química , Litio/química , Nitrilos/química , Potasio/química , Pirimidinas/síntesis química , Ciclopentanos/química , Iminas/química , Estructura Molecular , Pirimidinas/químicaRESUMEN
The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems.