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

…, S Lui, RJ Kleiman, M Vanase-Frawley…

Index: Claffey, Michelle M.; Helal, Christopher J.; Verhoest, Patrick R.; Kang, Zhijun; Fors, Kristina S.; Jung, Stanley; Zhong, Jiaying; 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; Oconnor, Rebecca E.; MacDougall-Murphy, Mary; Fonseca, Kari R.; Becker, Stacey L.; Nelson, Frederick R.; Liras, Spiros Journal of Medicinal Chemistry, 2012 , vol. 55, # 21 p. 9055 - 9068

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Citation Number: 28

Abstract

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's 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 ...