Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that hydrolyzes endocannabinoids. It has been shown that inhibition of FAAH produces analgesic and anti-inflammatory effects. The soluble epoxide hydrolase (sEH) enzyme hydrolases arachidonic acid metabolites epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids. EETs are known for their anti-inflammatory properties, thus inhibition of sEH consequently also reduces inflammation. Concurrent inhibition of both enzymes with dual inhibitor may represent a novel approach in the treatment of chronic pain. Drugs with multiple targets can provide a superior therapeutic effect and decrease in side effect profile compared to ligands with single target. Previously, we employed microwave-assisted methodologies to synthesize libraries of benzothiazole analogs, and were able to identify several dual inhibitors possessing high affinity for both enzymes (e.g. 3, sEH IC50 = 9.6 nM; FAAH IC50 = 7 nM). In this study, we tested dual inhibitor 3 in the Formalin Test, rat model of acute inflammatory pain, and we designed a new library of dual inhibitors to test the importance of benzothiazole moiety. The data indicate that the dual inhibitor 3 produces antinociception against the inflammatory phase of the Formalin Test in vivo and is metabolically stable following intraperitoneal administration in male rats. Further, antinociception produced by the high dose is comparable to that of ketoprofen, a traditional nonsteroidal anti-inflammatory drug. Our structure-activity relationship studies revealed that 4-phenylthiazole moiety is well tolerated in both enzymes, producing excellent inhibition potencies in low nanomolar range (analogs 6l-p).

Designed multiple ligands as potential therapeutics for treatment of chronic pain

ACS Spring 2022

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