Abstract
Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 510-527 |
| Number of pages | 18 |
| Journal | Bioorganic Chemistry |
| Volume | 76 |
| DOIs | |
| State | Published - Feb 1 2018 |
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Keywords
- Adamantane
- Inhibitor
- Isocyanate
- Soluble epoxide hydrolase
- Urea
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Drug Discovery
- Organic Chemistry
Cite this
Effects of adamantane alterations on soluble epoxide hydrolase inhibition potency, physical properties and metabolic stability. / Burmistrov, Vladimir; Morisseau, Christophe; Harris, Todd R.; Butov, Gennady; Hammock, Bruce D.
In: Bioorganic Chemistry, Vol. 76, 01.02.2018, p. 510-527.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effects of adamantane alterations on soluble epoxide hydrolase inhibition potency, physical properties and metabolic stability
AU - Burmistrov, Vladimir
AU - Morisseau, Christophe
AU - Harris, Todd R.
AU - Butov, Gennady
AU - Hammock, Bruce D.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds.
AB - Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds.
KW - Adamantane
KW - Inhibitor
KW - Isocyanate
KW - Soluble epoxide hydrolase
KW - Urea
UR - http://www.scopus.com/inward/record.url?scp=85039983208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039983208&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2017.12.024
DO - 10.1016/j.bioorg.2017.12.024
M3 - Article
AN - SCOPUS:85039983208
VL - 76
SP - 510
EP - 527
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
SN - 0045-2068
ER -