Zhao Peng, Liu Dong, Song Chunying, Li Di, Zhang Xinzhu, Horecny Ivana, Zhang Fengqi, Yan Yuna, Zhuang Linghang, Li Jing, Liu Suxing, Mao Yuchang, Feng Jun, Liu Jian, Tao Weikang
Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States.
Shanghai Hengrui Pharmaceutical Co. Ltd., 279 Wenjing Road, Shanghai 200245, China.
ACS Pharmacol Transl Sci. 2022 Jun 22;5(7):458-467. doi: 10.1021/acsptsci.2c00023. eCollection 2022 Jul 8.
Osteoarthritis (OA) treatment is a highly unmet medical need. Development of a disease-modifying OA drug (DMOAD) is challenging with no approved drugs on the market. Inhibition of ADATMS-4/5 is a promising OA therapeutics to target cartilage degradation and potentially can reduce joint pain and restore its normal function. Starting from the reported ADAMTS-5 inhibitor GLPG1972, we applied a scaffold hopping strategy to generate a novel isoindoline amide scaffold. Representative compound showed high potency in ADATMS-4/5 inhibition, as well as good selectivity over a panel of other metalloproteases. In addition, compound exhibited excellent druglike properties and showed better pharmacokinetic (PK) profiles than GLPG1972 cross-species. Compound demonstrated dose-dependent efficacy in two rat osteoarthritis models.
骨关节炎（OA）的治疗是一项尚未得到满足的重大医疗需求。开发一种改善病情的骨关节炎药物（DMOAD）具有挑战性，目前市场上尚无获批药物。抑制ADATMS-4/5是一种有前景的骨关节炎治疗方法，可针对软骨降解，有可能减轻关节疼痛并恢复其正常功能。从已报道的ADAMTS-5抑制剂GLPG1972出发，我们应用了骨架跃迁策略来生成一种新型异吲哚啉酰胺骨架。代表性化合物在抑制ADATMS-4/5方面表现出高效力，并且对一系列其他金属蛋白酶具有良好的选择性。此外，该化合物表现出优异的类药性质，并且在跨物种方面显示出比GLPG1972更好的药代动力学（PK）特征。该化合物在两种大鼠骨关节炎模型中显示出剂量依赖性疗效。
