PDBsum entry 4e90

Hydrolase/hydrolase inhibitor

PDB id: 4e90

Contents

Protein chain

328 a.a.

Ligands

7RG ×2

Metals

_ZN ×2

_MG ×2

Waters ×313

PDB id:

4e90

Name:

Hydrolase/hydrolase inhibitor

Title:

Human phosphodiesterase 9 in complex with inhibitors

Structure:

High affinity cgmp-specific 3',5'-cyclic phosphodiesterase 9a. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde9a

Resolution:

2.50Å R-factor: 0.193 R-free: 0.216

Authors:

S.Liu

Key ref:

M.M.Claffey et al. (2012). 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. PubMed id: 23025719

Date:

20-Mar-12 Release date: 27-Feb-13

Protein chains

O76083  (PDE9A_HUMAN) -  High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A from Homo sapiens

Seq: 593 a.a.

Struc: 328 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.4.35 - 3',5'-cyclic-GMP phosphodiesterase.
• Reaction: 3',5'-cyclic GMP + H2O = GMP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Med Chem 55:9055-9068 (2012)

PubMed id: 23025719

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

M.M.Claffey, C.J.Helal, P.R.Verhoest, Z.Kang, K.S.Fors, S.Jung, J.Zhong, M.W.Bundesmann, X.Hou, S.Lui, R.J.Kleiman, M.Vanase-Frawley, A.W.Schmidt, F.Menniti, C.J.Schmidt, W.E.Hoffman, M.Hajos, L.McDowell, R.E.O'Connor, M.Macdougall-Murphy, K.R.Fonseca, S.L.Becker, F.R.Nelson, S.Liras.

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.