4E90

Human phosphodiesterase 9 in complex with inhibitors

Summary for 4E90

• Entry DOI: 10.2210/pdb4e90/pdb
• Related: 3JSW
• Descriptor: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform PDE9A1: Cell projection, ruffle membrane. Isoform PDE9A2: Cell projection, ruffle membrane. Isoform PDE9A3: Cytoplasm. Isoform PDE9A17: Cytoplasm: O76083
• Total number of polymer chains: 2
• Total formula weight: 78696.20

Authors

Liu, S. (deposition date: 2012-03-20, release date: 2013-02-27, Last modification date: 2024-02-28)

Primary citation

Claffey, M.M.,Helal, C.J.,Verhoest, P.R.,Kang, Z.,Fors, K.S.,Jung, S.,Zhong, J.,Bundesmann, M.W.,Hou, X.,Lui, S.,Kleiman, R.J.,Vanase-Frawley, M.,Schmidt, A.W.,Menniti, F.,Schmidt, C.J.,Hoffman, W.E.,Hajos, M.,McDowell, L.,O'Connor, R.E.,Macdougall-Murphy, M.,Fonseca, K.R.,Becker, S.L.,Nelson, F.R.,Liras, S.
Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.
J.Med.Chem., 55:9055-9068, 2012

PubMed 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.

PubMed: 23025719
DOI: 10.1021/jm3009635

Experimental method

X-RAY DIFFRACTION (2.5 Å)