Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists
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Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists. / Ieremias, Loukas; Kaspersen, Mads H.; Manandhar, Asmita; Schultz-Knudsen, Katrine; Vrettou, Christina Ioanna; Pokhrel, Rina; Heidtmann, Christoffer V.; Jenkins, Laura; Kanellou, Christina; Marsango, Sara; Li, Yueming; Bräuner-Osborne, Hans; Rexen Ulven, Elisabeth; Milligan, Graeme; Ulven, Trond.
In: Journal of Medicinal Chemistry, Vol. 67, No. 5, 2024, p. 3542-3570.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structure-Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists
AU - Ieremias, Loukas
AU - Kaspersen, Mads H.
AU - Manandhar, Asmita
AU - Schultz-Knudsen, Katrine
AU - Vrettou, Christina Ioanna
AU - Pokhrel, Rina
AU - Heidtmann, Christoffer V.
AU - Jenkins, Laura
AU - Kanellou, Christina
AU - Marsango, Sara
AU - Li, Yueming
AU - Bräuner-Osborne, Hans
AU - Rexen Ulven, Elisabeth
AU - Milligan, Graeme
AU - Ulven, Trond
N1 - Publisher Copyright: © 2024 American Chemical Society
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.3c01923
DO - 10.1021/acs.jmedchem.3c01923
M3 - Journal article
C2 - 38381650
AN - SCOPUS:85186107323
VL - 67
SP - 3542
EP - 3570
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -
ID: 387026154