2. Academic Validation
  3. Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF-α and IL-6 Release

Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF-α and IL-6 Release

  • J Med Chem. 2024 Sep 26;67(18):16185-16194. doi: 10.1021/acs.jmedchem.4c01007.
Joshua M Nicholson 1,  Dexi Yang 2,  Thomas Koelblen 3,  Eric L Hu 4,  Christopher C Coss 5,  Thomas P Burris 3,  Xiao Hu 6,  Glenn C Micalizio 1
Affiliations

Affiliations

  • 1 6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States.
  • 2 Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
  • 3 University of Florida Genetics Institute, Gainesville, Florida 32610, United States.
  • 4 Computational Biology Undergraduate Concentration, Brown University, 69 Brown Street, Mail no. 4277, Providence, Rhode Island 02912, United States.
  • 5 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 6 Accunet LLC BioPharma Consulting, 1805 Olive Green Street, Chula Vista, California 91913, United States.
PMID: 39240657 DOI: 10.1021/acs.jmedchem.4c01007
Abstract

Natural products are widely recognized as valuable starting points for the development of therapeutics, with synthetic Tetracyclic Triterpenoids (e.g., Steroids) being the most well represented among the drugs approved by the Food and Drug Administration. Here, recently developed synthetic tools for concise, asymmetric, and convergent construction of steroidal systems are leveraged to drive a program aimed at identifying novel Glucocorticoid Receptor (GR) modulators. While glucocorticoids have been extensively used as anti-inflammatory agents, they are plagued by severe side effects that include bone loss, muscle wasting, and Metabolic Disease. Ultimately, a program targeting the unnatural enantiomers of estranes (ent-estranes) that are practically inaccessible from natural product derivatization (semisynthesis) has resulted in the identification of a new class of potent dissociated GR modulators. We identify several leads with >99% efficacy as antagonists of GR trans-activation (potency within 10-fold of that of mifepristone) and further characterize examples that also inhibit release of pro-inflammatory cytokines IL-6 and TNF-α.

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