Bioorganic & Medicinal Chemistry Letters
Adamantyl thioureas as soluble epoxide hydrolase inhibitors
,
Robert R. Fayzullinf, Gennady M. Butovb, Bruce D. Hammocka,⁎
a
Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
b
Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch) Volgograd State Technical University, Volzhsky
404121, Russia
c
Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Moscow 143026, Russia
Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia
Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region 142432, Russia
d
e
f
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of Russian Academy of Sciences, Kazan 420088, Russia
A R T I C L E I N F O
A B S T R A C T
Keywords:
Soluble epoxide hydrolase
Inhibitor
Adamantane
Isothiocyanate
Thiourea
A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been
developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)
bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The
inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather
than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them
more bioavailable and thus promising as sEH inhibitors.
Mammalian soluble epoxide hydrolase (sEH, E.C. 3.3.2.10) is in-
volved in the metabolism of epoxy-fatty acids to the corresponding
vicinal diols through the reaction with a water molecule.1,2 Endogenous
substrates for the sEH include cytochrome P450 metabolites of ara-
chidonic (epoxyeicosatrienoic acids, EETs) and docosahexaenoic
(epoxydocosatrienoic acids, EDPEs) acids.3,4 EETs possess vasodilatory
The common structure of known sEH thiourea based inhibitor is Ad-
cyclic group.18–21 While the R-group was altered, the left (adamantane)
part of the thiourea molecules was the same in almost all known
thioureas based sEH inhibitors. Thus, the impact of alterations in ada-
mantyl part of the thioureas on their potency and properties has never
been investigated.
effects through the activation of the calcium dependent broad K+
-
channels in endothelial cells, which are beneficial in many renal and
cardiovascular diseases.5,6 Furthermore, the EETs have some anti-in-
flammatory and analgesic properties.7 Their conversion to dihydrox-
yeicosatrienoic acids (DHETs) by sEH reduces those beneficial activ-
ities. The inhibition of sEH in vivo by highly selective inhibitors results
in an increase of the concentration of the EETs and other epoxy fatty
acids and is accompanied by a reduction in angiotensin driven blood
pressure in rodents, but also reduction of inflammatory and painful
states, thereby suggesting that sEH is a target for the treatment of hy-
pertension, inflammatory diseases and pain.8–10
Most of compounds reported as sEH inhibitors are 1,3-disubstituted
ureas.11–15 To our knowledge, only 10 thioureas have been reported as
sEH inhibitors16,17 compared to thousands of ureas. Thus, a systematic
investigation of thioureas as sEH inhibitors is needed. Separately, ureas
are difficult to formulate because of their high melting points and low
water solubility. Herein, we investigate the influence of a thiourea
function on the physical properties in comparison to ureas.
In this work we prepared and systematically studied new structural
types of adamantyl thioureas with the following features: (i) spacers
between adamantyl substituent and thiourea group to enhance con-
formational mobility; (ii) alkyl substituents in the bridgehead positions
of adamantane to alter its lipophilicity; (iii) two adamantyl parts in a
single molecule; (iv) adamantyl fragment linked with thioureas group
by the bridge carbon; (v) aromatic fragments to regulate lipophilicity.
Reaction of amines with isothiocyanates is among the most widely
used procedures for the preparation of thioureas. In contrast to iso-
in common conditions.22 Due to the bimolecular nature of this reaction,
the adamantane moiety can be introduced in to the molecule of
thiourea either with adamantyl amine or with adamantyl iso-
thiocyanate. In this case, it is reasonable to use adamantyl amines,
which are quite available in contrast to the adamantyl iso-
thiocyanates.23 Since the mechanism of thiourea formation is nucleo-
philic addition to thiocarbonyl group, the most significant factors
⁎
Corresponding author.
Received 26 February 2018; Received in revised form 30 March 2018; Accepted 10 May 2018
Pleasecitethisarticleas:Burmistrov,V.,Bioorganic&MedicinalChemistryLetters(2018),https://doi.org/10.1016/j.bmcl.2018.05.024