Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches

• Published in: Journal of medicinal chemistry Vol. 63; no. 23; pp. 15050 - 15071
• Main Authors: Xiao, Hai-Yun, Li, Ning, Duan, James J.-W, Jiang, Bin, Lu, Zhonghui, Ngu, Khehyong, Tino, Joseph, Kopcho, Lisa M, Lu, Hao, Chen, Jing, Tebben, Andrew J, Sheriff, Steven, Chang, ChiehYing Y, Yanchunas, Joseph, Calambur, Deepa, Gao, Mian, Shuster, David J, Susulic, Vojkan, Xie, Jenny H, Guarino, Victor R, Wu, Dauh-Rurng, Gregor, Kurt R, Goldstine, Christine B, Hynes, John, Macor, John E, Salter-Cid, Luisa, Burke, James R, Shaw, Patrick J, Dhar, T. G. Murali
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2020; Amer Chemical Soc
• Subjects: Animals; Arthritis, Experimental - drug therapy; Arthritis, Rheumatoid - drug therapy; Chemistry, Medicinal; Drug Design; Female; Humans; Life Sciences & Biomedicine; Mice, Inbred C57BL; Microsomes, Liver - metabolism; Molecular Structure; Naphthyridines - chemical synthesis; Naphthyridines - pharmacokinetics; Naphthyridines - pharmacology; Naphthyridines - therapeutic use; Pharmacology & Pharmacy; Proof of Concept Study; Quinolines - chemical synthesis; Quinolines - pharmacokinetics; Quinolines - pharmacology; Quinolines - therapeutic use; Science & Technology; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism; SUPERFAMILY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01732

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure–activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic–pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.