2. Academic Validation
  3. Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists

Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists

  • J Med Chem. 2024 Feb 21. doi: 10.1021/acs.jmedchem.3c01923.
Loukas Ieremias 1,  Mads H Kaspersen 1 2,  Asmita Manandhar 1,  Katrine Schultz-Knudsen 1,  Christina Ioanna Vrettou 1,  Rina Pokhrel 1,  Christoffer V Heidtmann 2,  Laura Jenkins 3,  Christina Kanellou 1,  Sara Marsango 1,  Yueming Li 3,  Hans Bräuner-Osborne 1,  Elisabeth Rexen Ulven 1,  Graeme Milligan 3,  Trond Ulven 1 2
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, Faculty of Health, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Copenhagen, Denmark.
  • 2 Department of Physics, Chemistry and Pharmacy, Faculty of Science, University of Southern Denmark, Campusvej 55, 5230 Odense M, Odense, Denmark.
  • 3 School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.
PMID: 38381650 DOI: 10.1021/acs.jmedchem.3c01923
Abstract

GPR84 is a putative medium-chain fatty acid receptor that is implicated in regulation of inflammation and fibrogenesis. Studies have indicated that GPR84 agonists may have therapeutic potential in diseases such as Alzheimer's disease, atherosclerosis, and Cancer, but there is a lack of quality tool compounds to explore this potential. The fatty acid analogue LY237 (4a) is the most potent GPR84 Agonist disclosed to date but has unfavorable physicochemical properties. We here present a SAR study of 4a. Several highly potent agonists were identified with EC50 down to 28 pM, and with SAR generally in excellent agreement with structure-based modeling. Proper incorporation of rings and polar groups resulted in the identification of TUG-2099 (4s) and TUG-2208 (42a), both highly potent GPR84 agonists with lowered lipophilicity and good to excellent solubility, in vitro permeability, and microsomal stability, which will be valuable tools for exploring the pharmacology and therapeutic prospects of GPR84.

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