Discovery of a Potent and in Vivo Anti-inflammatory Efficacious, P2Y14R Antagonist with a Novel Benzisoxazoles Scaffold by DNA-Encoded Chemical Library Technology

Abstract

P2Y₁₄R is activated by UDP (uridine diphosphate) and UDP glucose and associated with the development of many inflammatory diseases. P2Y₁₄R antagonists are expected to be a new choice for the treatment of inflammatory diseases. A DNA-encoded chemical library (DEL) of 4 billion molecules was screened, leading to the identification of compound A, a novel benzisoxazole scaffold-based P2Y₁₄ antagonist with an IC₅₀ value of 23.60 nM. Binding mode analysis and SPR analysis (KD = 7.26 μM) demonstrated that Compound A bind strongly to P2Y₁₄R. ‌Molecular dynamics simulations and binding free energy calculations were performed to analyze the binding mode of Compound A with P2Y₁₄R. And in the LPS-induced acute lung injury mice, after treatment with Compound A, the degree of lung injury was greatly reduced, the infiltration of immune cells was decreased, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased. Compound A exhibited good P2Y₁₄R antagonist activity, demonstrated efficacy both in vitro and in vivo, possessed favorable druggability, and featured a novel benzisoxazole scaffold with potential for further optimization, providing a new strategy for developing subsequent P2Y14 antagonists.