Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China; State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
Eur J Med Chem. 2022 Jan 5;227:113933. doi: 10.1016/j.ejmech.2021.113933. Epub 2021 Oct 19.
The P2Y nucleotide receptor, a subtype of P2Y receptors, is implicated in many human inflammatory diseases. Based on the identification of favorable residues of two screening hits in the almost symmetrical P2Y binding domain, we describe the structural optimization of previously identified virtual screening hits 6 and 7 that result in the development of P2YR antagonists with a novel 2-phenyl-benzoxazole acetamide chemical scaffold. Notably, compound 52 showed potent P2YR antagonistic activity (IC = 2 nM), and a stronger inhibitory effect on MSU-induced inflammatory in vitro, better than a previously described P2YR antagonist PPTN. In vivo evaluation demonstrated that compound 52 also had satisfactory inhibitory activity on the inflammatory response of gout flares in mice. Moreover, P2YR antagonist 52 decreased paw swelling and inflammatory cell infiltration through cAMP/NLRP3/GSDMD signaling pathways in MSU-induced acute gouty arthritis mice. The discussions on the binding mechanism that employ MM/GBSA free energy calculations/decompositions also provide some useful clues for further structural designing of compound 52. Taken together, 2-phenyl-benzoxazole acetamide derivative 52 with potent P2YR antagonistic activity and in vivo potency could be a promising strategy for gout therapy and deserves further optimization.
P2Y 核苷酸受体是 P2Y 受体的一种亚型，与许多人类炎症性疾病有关。基于对两个筛选命中物在几乎对称的 P2Y 结合域中有利残基的鉴定，我们描述了先前鉴定的虚拟筛选命中物 6 和 7 的结构优化，这导致了具有新型 2-苯基-苯并恶唑乙酰胺化学支架的 P2YR 拮抗剂的开发。值得注意的是，化合物 52 表现出很强的 P2YR 拮抗活性（IC50 = 2 nM），并且对 MSU 诱导的体外炎症具有更强的抑制作用，优于先前描述的 P2YR 拮抗剂 PPTN。体内评价表明，化合物 52 对小鼠痛风发作的炎症反应也具有令人满意的抑制作用。此外，P2YR 拮抗剂 52 通过 cAMP/NLRP3/GSDMD 信号通路降低了 MSU 诱导的急性痛风性关节炎小鼠的足肿胀和炎症细胞浸润。使用 MM/GBSA 自由能计算/分解的结合机制讨论也为进一步的化合物 52 结构设计提供了一些有用的线索。总之，具有强 P2YR 拮抗活性和体内活性的 2-苯基-苯并恶唑乙酰胺衍生物 52 可能是治疗痛风的一种很有前途的策略，值得进一步优化。
