Evaluation of the Therapeutic Potential of Sulfonyl Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors.

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.

One-Pot Synthesis of Thio-Augmented Sulfonylureas via a Modified Bunte's Reaction.

We report the development of a one-pot Bunte's reaction-enabled expeditious platform under aqueous conditions for the scalable conversion of sulfonylureas to synthetically versatile thio-sulfonylureas. The reaction was further propagated in the same pot to yield diverse chiral and achiral isothiosulfonyl analogs. The protocol enabled the synthesis of various drug-like molecules and was applied to an enantiomeric synthesis of a cannabinoid receptor antagonist SLV326.

Soluble epoxide hydrolase inhibitors: an overview and patent review from the last decade.

INTRODUCTION: Biological effects mediated by the CYP450 arm of arachidonate cascade implicate the enzyme-soluble epoxide hydrolase (sEH) in hydrolyzing anti-inflammatory epoxy fatty acids to pro-inflammatory diols. Hence, inhibiting the sEH offers a therapeutic approach to treating inflammatory diseases. Over three decades of work has shown the role of sEH inhibitors (sEHis) in treating various disorders in rodents and larger veterinary subjects. Novel chemical strategies to enhance the efficacy of sEHi have now appeared. AREAS COVERED: A comprehensive review of patent literature related to soluble epoxide hydrolase inhibitors in the last decade (2010-2021) is provided. EXPERT OPINION: Soluble epoxide hydrolase (sEH) is an important enzyme that metabolizes the bioactive epoxy fatty acids (EFAs) in the arachidonic acid signaling pathway and converts them to vicinal diols, which appear to be pro-inflammatory. Inhibition of sEH hence offers a mechanism to increase in vivo epoxyeicosanoid levels and resolve pro-inflammatory pathways in disease states. Significant efforts in the field have led to potent single target as well as multi-target inhibitors with promising in vitro and widely encompassing in vivo activities. Successful clinical translation of compounds targeting sEH inhibition will further validate the promised therapeutic potential of this pathway in treating human diseases.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CB1R) Receptor with Reduced Lipophilicity.

In the present report, we describe the synthesis and structure-activity relationships of novel "four-arm" dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CB1R). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB1 receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CB1R and potent in vitro CB1R antagonist activities. Promising compounds with potent CB1R activity were evaluated in tissue distribution studies. Compounds 6a, 6f, and 7c showed limited brain penetrance attesting to its peripheral restriction. The 4S-enantiomer of these compounds further showed a stereoselective affinity for the CB1 receptor and behaved as inverse agonists. In vivo studies on food intake and body weight reduction in diet-induced obese (DIO) mice showed that these compounds could serve as potential leads for the development of selective CB1R antagonists with improved potency and peripheral restriction.

Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia.

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.

Recent progress in the discovery of ghrelin O-acyltransferase (GOAT) inhibitors.

Ghrelin is a stomach-derived peptide hormone which stimulates appetite. For ghrelin to exert its orexigenic effect, octanoylation on the serine-3 residue of this gut-brain peptide is essential. The octanoylation of ghrelin is mediated by a unique acyltransferase enzyme known as ghrelin O-acyltransferase (GOAT). Thus modulating this enzyme offers viable approaches to alter feeding behaviors. Over the past decade, several small-molecule based approaches have appeared dealing with the discovery of compounds able to modulate this enzyme for the treatment of obesity and type 2 diabetes. Drug discovery efforts from academic groups and several pharmaceutical companies have fielded compounds having efficacy in altering acylated ghrelin levels in animal models but to date, compounds modulating the activity of the GOAT enzyme do not yet represent clinical options. This mini-review covers the drug discovery approaches of the last decade since the discovery of the GOAT enzyme.