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PDBsum entry 4wcu
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PDB id:
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Hydrolase
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Title:
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Pde4 complexed with inhibitor
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Structure:
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Camp-specific 3',5'-cyclic phosphodiesterase 4d. Chain: a, b, c, d. Fragment: unp residues 179-398. Synonym: dpde3,pde43. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4d, dpde3. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.35Å
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R-factor:
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0.247
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R-free:
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0.304
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Authors:
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M.D.Sorensen
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Key ref:
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J.Felding
et al.
(2014).
Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis.
J Med Chem,
57,
5893-5903.
PubMed id:
DOI:
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Date:
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05-Sep-14
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Release date:
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08-Oct-14
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PROCHECK
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Headers
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References
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Q08499
(PDE4D_HUMAN) -
3',5'-cyclic-AMP phosphodiesterase 4D from Homo sapiens
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Seq:
Struc:
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809 a.a.
330 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.1.4.53
- 3',5'-cyclic-AMP phosphodiesterase.
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Reaction:
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3',5'-cyclic AMP + H2O = AMP + H+
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3',5'-cyclic AMP
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+
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H2O
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=
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AMP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
57:5893-5903
(2014)
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PubMed id:
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Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis.
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J.Felding,
M.D.Sørensen,
T.D.Poulsen,
J.Larsen,
C.Andersson,
P.Refer,
K.Engell,
L.G.Ladefoged,
T.Thormann,
A.M.Vinggaard,
P.Hegardt,
A.Søhoel,
S.F.Nielsen.
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ABSTRACT
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Development of orally available phosphodiesterase 4 (PDE4) inhibitors as
anti-inflammatory drugs has been going on for decades. However, only roflumilast
has received FDA approval. One key challenge has been the low therapeutic window
observed in the clinic for PDE4 inhibitors, primarily due to PDE4 mediated side
effects. Here we describe our approach to circumvent this issue by applying a
soft-drug concept in the design of a topically acting PDE4 inhibitor for
treatment of dermatological diseases. We used a fast follower approach, starting
from piclamilast. In particular, simultaneous introduction of 2'-alkoxy
substituents and changing an amide to a keto linker proved to be beneficial when
designing potential soft-drug candidates. This effort culminated in
identification of LEO 29102 (20), a potent, selective, and soft-drug PDE4
inhibitor with properties suitable for patient-friendly formulations giving
efficient drug delivery to the skin. Compound 20 has reached phase 2 and
demonstrated clinically relevant efficacy in the treatment of atopic dermatitis.
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