학술논문
Application of Structure-BasedDrug Design and ParallelChemistry to Identify Selective, Brain Penetrant, In Vivo Active Phosphodiesterase9A Inhibitors.
Document Type
Article
Author
Claffey, Michelle M.; Helal, Christopher J.; Verhoest, PatrickR.; Kang, Zhijun; Bundesmann, Mark W.; Hou, Xinjun; Lui, Shenping; Kleiman, Robin J.; Vanase-Frawley, Michelle; Schmidt, Anne W.; Menniti, Frank; Schmidt, Christopher J.; Hoffman, William E.; Hajos, Mihaly; McDowell, Laura; O’Connor, Rebecca E.; MacDougall-Murphy, Mary; Fonseca, Kari R.; Becker, Stacey L.; Nelson, FrederickR.
Source
Subject
*DRUG design
*PHOSPHODIESTERASE inhibitors
*ALZHEIMER'S disease treatment
*CYCLIC guanylic acid
*PHARMACEUTICAL chemistry
*CENTRAL nervous system
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Language
ISSN
0022-2623
Abstract
Phosphodiesterase 9A inhibitors have shown activity inpreclinicalmodels of cognition with potential application as novel therapiesfor treating Alzheimer’s disease. Our clinical candidate, PF-04447943(2), demonstrated acceptable CNS permeability in ratswith modest asymmetry between central and peripheral compartments(free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemicalproperties outside the range associated with traditional CNS drugs.To address the potential risk of restricted CNS penetration with 2in human clinical trials, we sought to identify a preclinicalcandidate with no asymmetry in rat brain penetration and that couldadvance into development. Merging the medicinal chemistry strategiesof structure-based design with parallel chemistry, a novel seriesof PDE9A inhibitors was identified that showed improved selectivityover PDE1C. Optimization afforded preclinical candidate 19that demonstrated free brain/free plasma ≥1 in rat and reducedmicrosomal clearance along with the ability to increase cyclic guanosinemonophosphosphate levels in rat CSF. [ABSTRACT FROM AUTHOR]