2. Academic Validation
  3. Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators

Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators

  • J Med Chem. 2025 Jul 24;68(14):14357-14383. doi: 10.1021/acs.jmedchem.5c00323.
Zhiguo Bian 1,  Robert G Schmidt 1,  Noel S Wilson 1,  David B Duignan 2,  Eric Breinlinger 2,  Amanda W Dombrowski 1,  Paul Erdman 1,  C Michael Foley 1,  Michael Friedman 2,  Gregory A Gfesser 1,  Christian A Goess 2,  Arthur Gomtsyan 1,  Russell A Judge 1,  Ryota Kikuchi 1,  Yevgeniya Koshman 1,  Xiaoqin Liu 1,  Kenton L Longenecker 1,  Andrea McClure 1,  Kevin Sippy 1,  Jill M Wetter 1,  Robert Stoffel 1,  Anil Vasudevan 1
Affiliations

Affiliations

  • 1 AbbVie Inc, North Chicago, Illinois 60064, United States.
  • 2 AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States.
PMID: 40632677 DOI: 10.1021/acs.jmedchem.5c00323
Abstract

Tumor necrosis factor α (TNFα) plays a critical role in inflammatory and autoimmune diseases. While biologic drugs have improved patient outcomes in conditions like rheumatoid arthritis by disrupting TNFα signaling, small molecule targeting has been challenging due to the strong TNF-receptor binding and difficulty in disrupting the TNF trimer. This research presents small molecule TNFα inhibitors with a novel bridged-piperazine core, developed through molecular dynamics simulation and scaffold hopping. The initial hit was optimized using structure-based design, leading to the discovery of a lead molecule with similar potency to the prototype but enhanced physicochemical properties. This lead demonstrated oral efficacy in a mouse glucose-6-phosphate isomerase-induced paw swelling model, comparable to the effects of a TNFα antibody. The estimated effective human dose is 200 mg once daily, highlighting the potential for clinical development of these compounds.

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