A systematic investigation of the stereoselectivity in Lewis acid-promoted (Mukaiyama) aldol reactions of achiral unsubstituted enolsilanes and chiral beta-hydroxy aldehydes proceeding under conditions favoring chelation control is presented. Good stereocontrol can be realized for enolsilane aldol reactions of beta-alkoxy and beta-silyloxy aldehydes bearing only an alpha- or a beta-stereogenic center. Examination of the chelated intermediates for alpha,beta-disubstituted aldehydes concludes that the syn aldehyde diastereomer possesses the arrangement of stereocenters wherein the alpha- and beta-substituents impart a reinforcing facial bias upon the aldehyde carbonyl. Aldol reactions of syn aldehydes were thus observed to proceed with uniformly excellent diastereofacial selectivity. Aldol reactions of the corresponding anti aldehydes containing opposing stereocontrol elements at the alpha- and beta-positions exhibit variable and unpredictable selectivity.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.

No abstract

No abstract

No abstract