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

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

  • J Med Chem. 2012 Nov 8;55(21):9055-68. doi: 10.1021/jm3009635.
Michelle M Claffey 1,  Christopher J Helal,  Patrick R Verhoest,  Zhijun Kang,  Kristina S Fors,  Stanley Jung,  Jiaying Zhong,  Mark W Bundesmann,  Xinjun Hou,  Shenping Lui,  Robin J Kleiman,  Michelle Vanase-Frawley,  Anne W Schmidt,  Frank Menniti,  Christopher J Schmidt,  William E Hoffman,  Mihaly Hajos,  Laura McDowell,  Rebecca E O'Connor,  Mary Macdougall-Murphy,  Kari R Fonseca,  Stacey L Becker,  Frederick R Nelson,  Spiros Liras
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. michelle.m.claffey@pfizer.com
PMID: 23025719 DOI: 10.1021/jm3009635
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 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.

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