Xiao Yufang, Karra Srinivasa, Goutopoulos Andreas, Morse Noune Tahmassian, Zhang Susan, Dhanabal Mohanraj, Tian Hui, Seenisamy Jeyaprakashnarayanan, Jayadevan Jayashankaran, Caldwell Richard, Potnick Justin, Bleich Matthew, Chekler Eugene, Sherer Brian, Sriraman Venkataraman
EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States.
Bioorg Med Chem Lett. 2019 Jul 1;29(13):1660-1664. doi: 10.1016/j.bmcl.2019.04.033. Epub 2019 Apr 24.
The P2X7 receptor (P2X7R) plays an important role in diverse conditions associated with tissue damage and inflammation, suggesting that the human P2X7R (hP2X7R) is an attractive therapeutic target. In the present study, the synthesis and structure-activity relationship (SAR) of a novel series of quinoline derivatives as P2X7R antagonists are described herein. These compounds exhibited mechanistic activity (YO PRO) in an engineered HEK293 expressing hP2X7R as well as a functional response (IL-1β) in human THP-1 (hTHP-1) cellular assays. Compound 19 was identified as the most promising compound in this series with excellent cellular potency, low liver microsomal clearance, good permeability and low efflux ratio. In addition, this compound also displayed good pharmacokinetic properties and acceptable brain permeability (K of 0.37).
P2X7受体（P2X7R）在与组织损伤和炎症相关的多种病症中发挥着重要作用，这表明人P2X7受体（hP2X7R）是一个有吸引力的治疗靶点。在本研究中，本文描述了一系列新型喹啉衍生物作为P2X7R拮抗剂的合成及构效关系（SAR）。这些化合物在表达hP2X7R的工程化HEK293细胞中表现出机制活性（YO PRO），并且在人THP-1（hTHP-1）细胞试验中表现出功能性反应（IL-1β）。化合物19被确定为该系列中最有前景的化合物，具有优异的细胞活性、低肝微粒体清除率、良好的通透性和低外排率。此外，该化合物还表现出良好的药代动力学性质和可接受的脑通透性（K为0.37）。
