Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
J Med Chem. 2021 Mar 25;64(6):2937-2952. doi: 10.1021/acs.jmedchem.0c02008. Epub 2021 Mar 15.
There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5 is a promising target for the identification of DMOADs. We describe the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5 inhibitor obtained by optimization of a promising hydantoin series following an HTS. Biochemical activity against rat and human ADAMTS-5 was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity was confirmed with human aggrecan using an AGC ELISA. The most promising compounds were selected based on reduction of glycosaminoglycan release after interleukin-1 stimulation in mouse cartilage explants and led to the discovery of GLPG1972/S201086. The anticatabolic activity was confirmed in mouse cartilage explants (IC < 1.5 μM). The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clinical study in patients with knee OA (NCT03595618).
目前尚无被批准的治疗骨关节炎（OA）的药物（DMOAD）。聚集蛋白聚糖酶 ADAMTS-5 是降解人聚集蛋白聚糖（AGC）的关键酶，AGC 是软骨的组成成分。因此，ADAMTS-5 是鉴定 DMOAD 的有希望的靶点。我们描述了 GLPG1972/S201086 的发现，这是一种通过高通量筛选（HTS）对有前途的海因二酮系列进行优化获得的强效和选择性 ADAMTS-5 抑制剂。通过基于荧光的测定法评估了对大鼠和人 ADAMTS-5 的生化活性。使用 AGC ELISA 用人聚集蛋白聚糖证实了 ADAMTS-5 抑制活性。根据白细胞介素-1 刺激后小鼠软骨外植体中糖胺聚糖释放的减少，选择了最有前途的化合物，从而发现了 GLPG1972/S201086。在小鼠软骨外植体中证实了抗分解代谢活性（IC <1.5 μM）。讨论了 GLPG1972/S201086 与人重组 ADAMTS-5 的共晶结构。GLPG1972/S201086 已在膝关节骨关节炎患者的 2 期临床研究中进行了研究（NCT03595618）。
