Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund’s adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1′-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose (p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation.

A new procedure has been proposed for the synthesis of 3-chloroadamantan-1-ylmethyl isocyanate starting from 2-(3-chloroadamantan-1-yl)acetic acid. Reactions of 3-chloroadamantan-1-ylmethyl isocyanate with fluoro- and chloroanilines and alkane-α,ω-diamines afforded two series of N,N′-disubstituted ureas containing a 3-chloroadamantan-1-yl substituent in 53–94% yields. The synthesized ureas are promising as inhibitors of human soluble epoxide hydrolase.

A series of N,N′-disubstituted ureas and bis-ureas were synthesized in 36–85% yields by the reaction 3-bromoadamantan-1-yl isocyanate with α,ω-alkanediamines, fluorinated anilines, and trans-4-[(4-aminocyclo­hexyl)oxy]benzoic acid. The hydrolysis of 3-bromoadamant-1-yl isocyanate in the presence of a catalytic amount of DBU gave 60% of symmetrical N,N′-bis(3-bromoadamantan-1-yl)urea. The synthesized compounds are promising as inhibitors of human soluble epoxide hydrolase (hsEH).

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of bioactive lipid signaling molecules. sEH converts epoxyeicosatrienoic acids (EET) to virtually inactive dihydroxyeicosatrienoic acids (DHET). The first acids are “medicinal” molecules, the second increase the inflammatory infiltration of cells. Mitogen-activated protein kinases (p38 MAPKs) are key protein kinases involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an important role in the regulation of cellular processes, especially inflammation. The proto-oncogenic serine/threonine protein kinase Raf (c-Raf) is a major component of the mitogen-activated protein kinase (MAPK) pathway: ERK1/2 signaling. Normal cellular Raf genes can also mutate and become oncogenes, overloading the activity of MEK1/2 and ERK1/2. The development of multitarget inhibitors is a promising strategy for the treatment of socially dangerous diseases. We synthesized 1,3-disubstituted ureas and diureas containing a dichloroadamantyl moiety. The results of computational methods show that soluble epoxide hydrolase inhibitors can act on two more targets in different signaling pathways of mitogen-activated protein kinases p38 MAPK and c-Raf. The two chlorine atoms in the adamantyl moiety may provide additional Cl-π interactions in the active site of human sEH. Molecular dynamics studies have shown that the stability of ligand–protein complexes largely depends on the “spacer effect.” The compound containing a bridge between the chloroadamantyl fragment and the ureide group forms more stable ligand–protein complexes with sEH and p38 MAPK, which indicates a better conformational ability of the molecule in the active sites of these targets. In turn, a compound containing two chlorine atoms forms a more stable complex with c-Raf, probably due to the presence of additional halogen bonds of chlorine atoms with amino acid residues.

A one-step synthesis of 1-(isocyanatomethyl)-3,5-dimethyladamantane with a yield of 87% is described. The reaction of 1-(isocyanatomethyl)-3,5-dimethyladamantane with aliphatic diamines gave a series of symmetrical 1,3-disubstituted ureas with 63–99% yields. The synthesized ureas hold promise as human soluble epoxide hydrolase inhibitors.

A series of 1,3-disubstituted ureas containing a lipophilic adamantane moiety tethered to the ureido group by a methylene bridge were synthesized by the reaction of 1-(isocyanatomethyl)adamantane with monohalo- and dihaloanilines in yields of up to 92%. The synthesized ureas are target oriented inhibitors of human soluble epoxide hydrolase (sEH).