 |
PDBsum entry 5b25
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
5b25
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase/hydrolase inhibitor
|
|
|
Title:
|
|
Crystal structure of human pde1b with inhibitor 3
|
|
Structure:
|
|
Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1b. Chain: a, b, c, d. Fragment: unp residues 146-506. Synonym: cam-pde 1b. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: pde1b, pde1b1, pdes1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
|
|
Resolution:
|
|
|
1.90Å
|
R-factor:
|
0.173
|
R-free:
|
0.203
|
|
|
Authors:
|
|
K.Ida,W.Lane,G.Snell,S.Sogabe
|
|
Key ref:
|
|
P.Li
et al.
(2016).
Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.
J Med Chem,
59,
1149-1164.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
07-Jan-16
|
Release date:
|
03-Feb-16
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
Q01064
(PDE1B_HUMAN) -
Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
536 a.a.
335 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.3.1.4.17
- 3',5'-cyclic-nucleotide phosphodiesterase.
|
|
|
|
|
|
|
Reaction:
|
|
a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H+
|
|
|
|
|
|
nucleoside 3',5'-cyclic phosphate
Bound ligand (Het Group name = )
matches with 46.15% similarity
|
+
|
H2O
|
=
|
nucleoside 5'-phosphate
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
59:1149-1164
(2016)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.
|
|
P.Li,
H.Zheng,
J.Zhao,
L.Zhang,
W.Yao,
H.Zhu,
J.D.Beard,
K.Ida,
W.Lane,
G.Snell,
S.Sogabe,
C.J.Heyser,
G.L.Snyder,
J.P.Hendrick,
K.E.Vanover,
R.E.Davis,
L.P.Wennogle.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and
synthesized. The structure-activity relationships of these polycyclic compounds
as phosphodiesterase 1 (PDE1) inhibitors were studied along with their
physicochemical and pharmacokinetic properties. Systematic optimizations of this
novel scaffold culminated in the identification of a clinical candidate,
(6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one
phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1,
demonstrated excellent selectivity against all other PDE families and showed
good efficacy in vivo. Currently, this investigational new drug is in Phase I
clinical development and being considered for the treatment of several
indications including cognitive deficits associated with schizophrenia and
Alzheimer's disease, movement disorders, attention deficit and hyperactivity
disorders, and other central nervous system (CNS) and non-CNS disorders.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
