Development of novel NLRP3-XOD dual inhibitors for the treatment of gout

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126944. doi: 10.1016/j.bmcl.2019.126944.

Weiwei Wang ¹, Jing Pang ¹, Eun Hee Ha ¹, Mengze Zhou ², Zhubin Li ¹, Sheng Tian ¹, Huanqiu Li ³, Qinghua Hu ⁴

Affiliations

1 Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
2 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
3 Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China. Electronic address: [email protected].
4 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].

PMID: 31924495 DOI: 10.1016/j.bmcl.2019.126944

Abstract

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like Receptor protein 3 (NLRP3) inflammasome as Pattern Recognition Receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.

Keywords

Acute gouty arthritis; Dual inhibitors; Gout; Nod-like protein receptor 3.

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