biostudies-literatureUnknown5(7)Zhao PEternity Bioscience IncShanghai Hengrui Pharmaceutical Co. LtdOsteoarthritis (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 <b>18</b> showed high potency in ADATMS-4/5 inhibition, as well as good selectivity over a panel of other metalloproteases. In addition, compound <b>18</b> exhibited excellent druglike properties and showed better pharmacokinetic (PK) profiles than GLPG1972 cross-species. Compound <b>18</b> demonstrated dosACS pharmacology & translational science458-467https://www.ebi.ac.uk/biostudies/studies/S-EPMC9274773biostudies-literatureDiscovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis.PMC9274773Zhang FLiu JLi JLi DSong CLiu SYan YFeng JTao WHorecny IZhao PZhang XLiu DZhuang LMao YfalseDiscovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis.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 <b>18</b> showed high potency in ADATMS-4/5 inhibition, as well as good selectivity over a panel of other metalloproteases. In addition, compound <b>18</b> exhibited excellent druglike properties and showed better pharmacokinetic (PK) profiles than GLPG1972 cross-species. Compound <b>18</b> demonstrated dos2022-01-01T00:00:00Z2022 Jul2025-04-05T14:46:38.746Z2025-04-05T14:46:38.746ZS-EPMC92747733583713610.1021/acsptsci.2c00023