From the Design to the
Acute Disease
Adamantane
/ chemistry
Animals
Binding Sites
Catalytic Domain
Cell Membrane Permeability
/ drug effects
Drug Design
Drug Stability
Enzyme Inhibitors
/ chemistry
Epoxide Hydrolases
/ antagonists & inhibitors
Half-Life
Humans
Hydrophobic and Hydrophilic Interactions
Male
Mice
Mice, Inbred C57BL
Molecular Dynamics Simulation
Pancreatitis
/ drug therapy
Rats
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
13 05 2021
13 05 2021
Historique:
pubmed:
5
5
2021
medline:
17
6
2021
entrez:
4
5
2021
Statut:
ppublish
Résumé
The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an
Identifiants
pubmed: 33945278
doi: 10.1021/acs.jmedchem.0c01601
pmc: PMC8634379
doi:
Substances chimiques
Enzyme Inhibitors
0
Epoxide Hydrolases
EC 3.3.2.-
Adamantane
PJY633525U
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5429-5446Subventions
Organisme : NIEHS NIH HHS
ID : P42 ES004699
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103616
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107767
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES030443
Pays : United States
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