Preparation and evaluation of soluble epoxide hydrolase inhibitors with improved physical properties and potencies for treating diabetic neuropathic pain.
Bioorg Med Chem
; 28(22): 115735, 2020 11 15.
Article
in En
| MEDLINE
| ID: mdl-33007552
ABSTRACT
Soluble epoxide hydrolase (sEH), a novel therapeutic target for neuropathic pain, is a largely cytosolic enzyme that degrades epoxy-fatty acids (EpFAs), an important class of lipid signaling molecules. Many inhibitors of sEH have been reported, and to date, the 1,3-disubstituted urea has the highest affinity reported for the sEH among the central pharmacophores evaluated. An earlier somewhat water soluble sEH inhibitor taken to the clinic for blood pressure control had mediocre potency (both affinity and kinetics) and a short in vivo half-life. We undertook a study to overcome these difficulties, but the sEH inhibitors carrying a 1,3-disubstituted urea often suffer poor physical properties that hinder their formulation. In this report, we described new strategies to improve the physical properties of sEH inhibitors with a 1,3-disubstituted urea while maintaining their potency and drug-target residence time (a complementary in vitro parameter) against sEH. To our surprise, we identified two structural modifications that substantially improve the potency and physical properties of sEH inhibitors carrying a 1,3-disubstituted urea pharmacophore. Such improvements will greatly facilitate the movement of sEH inhibitors to the clinic.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetic Neuropathies
/
Enzyme Inhibitors
/
Epoxide Hydrolases
/
Hypoglycemic Agents
/
Neuralgia
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2020
Type:
Article
Affiliation country:
United States