Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors

Burmistrov, V. V.; Morisseau, Christophe; Karlov, Dmitry S.; Pitushkin, D. A.; Вернигора, А. А.; Rasskazova, E. V.; Бутов, Г. М.

doi:10.1016/j.bmcl.2020.127430

Cited by 19 publications

(10 citation statements)

References 17 publications

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“…This observation was further supported from SAR studies (EC5019 vs EC5023 in Table ). , Also, Lee et al revealed that the binding pocket of sEH is promiscuous, and the left side of the pocket can tolerate chemical structures of various sizes . The tunnel appears to breathe or even open to accept bulky groups.…”

Section: Biochemcal Mechanism Of Actionmentioning

confidence: 99%

“…5,19 Also, Lee et al revealed that the binding pocket of sEH is promiscuous, 30 and the left side of the pocket can tolerate chemical structures of various sizes. 31 The tunnel appears to breathe or even open to accept bulky groups. Therefore, EicOsis synthesized a new series of sEHI with a methyl substituent at the alpha-carbon of the piperidinyl amide of EC5023, resulting in a very potent EC5026 (Table 1).…”

Section: ■ Biochemcal Mechanism Of Actionmentioning

confidence: 99%

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Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative

Hammock¹,

McReynolds²,

Wagner³

et al. 2021

J. Med. Chem.

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This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transitionstate mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA in vivo and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammationresolving CYP450 branch of the arachidonate cascade.

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Section: Biochemcal Mechanism Of Actionmentioning

confidence: 99%

Section: ■ Biochemcal Mechanism Of Actionmentioning

confidence: 99%

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative

Hammock¹,

McReynolds²,

Wagner³

et al. 2021

J. Med. Chem.

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“…Urea derivatives containing fluorene and adamantane groups increased the sEH inhibitory activity by a factor of 4.5 [ 81 ]. The replacement of adamantyl and 4-(trifluoromethoxy)phenyl groups with natural bicyclic lipophilic groups provided a series of sEHIs with similar potency and 10-fold more water solubility compared to the original compounds [ 82 ]. On a similar note, Codony and coworkers developed 2-oxaadamant-1-yl urea-based molecules and reported that the replacement of a methylene unit of the adamantane group by an oxygen atom increased the solubility, permeability, and stability with nanomolar sEH inhibitory potency [ 83 ].…”

Section: Soluble Epoxide Hydrolase Inhibitors (Sehis)mentioning

confidence: 99%

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

2020

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The enzyme soluble epoxide hydrolase (sEH) plays a central role in metabolism of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH converts epoxyeicosatrienoic acids (EETs) to less bioactive dihydroxyeicosatrienoic acids. EETs exhibit anti-inflammatory, analgesic, antihypertensive, cardio-protective and organ-protective properties. Accordingly, sEH inhibition is a promising therapeutic strategy for addressing a variety of diseases. In this review, we describe small molecule architectures that have been commonly deployed as sEH inhibitors with respect to angiogenesis, inflammation and cancer. We juxtapose commonly used synthetic scaffolds and natural products within the paradigm of a multitarget approach for addressing inflammation and inflammation induced carcinogenesis. Structural insights from the inhibitor complexes and novel strategies for development of sEH-based multitarget inhibitors are also presented. While sEH inhibition is likely to suppress inflammation-induced carcinogenesis, it can also lead to enhanced angiogenesis via increased EET concentrations. In this regard, sEH inhibitors in combination chemotherapy are described. Urea and amide-based architectures feature prominently across multitarget inhibition and combination chemotherapy applications of sEH inhibitors.

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“…To resolve the existing problems of sEHI, numerous structural modifications were made. Among those modifications were the establishment of the basic structure of inhibitors [8] and various alterations of the lipophilic part of its molecules [7,9,10]. Compound EC5026 (Figure 1) containing the 3-fluoro-4-trifluorometoxyphenyl lipophilic group is in phase I human clinical trials as a new drug candidate intended to treat neuropathic pain [11].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Activity of Soluble Epoxide Hydrolase Inhibitors Based on Selenoureas Bearing an Adamantane Moiety

Burmistrov

Morisseau

Babkov

et al. 2022

IJMS

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Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors

Cited by 19 publications

References 17 publications

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Anti-Inflammatory Activity of Soluble Epoxide Hydrolase Inhibitors Based on Selenoureas Bearing an Adamantane Moiety

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