Stanley Jung

Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimers disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.

A superior synthesis of aspartame

Abstract The dipeptide sweetener, aspartame, has been prepared in high yield via the coupling of L-phenylalanine methyl ester and L-aspartic acid N-thiocarboxyanhydride.

A simple bis-annelation route to 3,4,5,6-tetrahydropyrido[3,2-c]quinolin-2-ones

Abstract A short, novel synthesis of the title ring system is described involving the intramolecular reaction of an amide dianion with a nitrile followed by in situ N-alkylation of the resultant intermediate.

Novel in vitro and in vivo inhibitors of prolyl endopeptidase

Abstract Inhibition of prolyl endopeptidase by Z-cyclohexyl prolinal and Z-indolinyl prolinal occurs with slow, tight binding inhibition and K i values of 2 – 3 nM. In vivo enzyme inhibition is also observed with a half time for recovery of enzyme activity of 3 – 4 h. Inhibition of prolyl endopeptidase by Z-cyclohexyl prolinal and Z-indolinyl prolinal occurs with slow, tight binding inhibition and K i values of 2 – 3 nM. In vivo enzyme inhibition is also observed with a half time for recovery of enzyme activity of 3 – 4 h.

An efficient synthesis of 1-phenyl-1-piperidino-trans-4-methylcyclohexane: Unanticipated total stereoselectivity in the catalytic hydrogenation of an olefin

Abstract A superior synthesis of the title compound, 1-phenyl-1-piperidino-trans-4-methylcyclohexane, is reported. The key step, the catalytic hydrogenation of 1-phenyl-1-piperidino-4-methylenecyclohexane hydrochloride, proceeds with unusual stereospecificity via addition of hydrogen trans to the axial phenyl substituent.