4G2L
Human PDE9 in complex with selective compound
Summary for 4G2L
| Entry DOI | 10.2210/pdb4g2l/pdb |
| Related | 3JSW |
| Descriptor | High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, ZINC ION, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | phosphodiesterase, inhibitor complex, cgmp->gmp, 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 | 78636.14 |
| Authors | |
| 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 Cited by 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: 23025719DOI: 10.1021/jm3009635 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
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