AC-261066

AC-261066 is a retinoic acid receptor β2 (RARβ2) agonist.¹ It selectively induces RARβ2 activity over RARβ1 activity in functional assays using mammalian cells (EC₅₀s = 10 and >10,000 nM, respectively). AC-261066 is also selective for RARβ over RARα and RARγ (EC₅₀s = 12, 70, and 33 nM, respectively, in transactivation assays).² Oral administration of AC-261066 (3 mg/100 ml in the drinking water) reduces infarct size, reperfusion arrhythmia duration, norepinephrine overflow, malondialdehyde (MDA) levels, and cardiac mast cell degranulation in a Langendorff isolated perfused mouse heart model of ischemia-reperfusion injury using ApoE^-/- mice.³ It reduces steatosis, hepatic 4-hydroxy nonenal (4-HNE) levels, and hepatic stellate cell activation in a mouse model of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet.⁴

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1. Lund, B.W., Piu, F., Gauthier, N.K., et al. Discovery of a potent, orally available, and isoform-selective retinoic acid β₂ receptor agonist. J. Med. Chem. 48(24), 7517-7519 (2005).

2. Goncalves, M.B., Clarke, E., Jarvis, C.I., et al. Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury. Bioorg. Med. Chem. Lett. 29(8), 995-1000 (2019).

3. Marino, A., Sakamoto, T., Tang, X.H., et al. A retinoic acid β₂-receptor agonist exerts cardioprotective effects. J. Pharmacol. Exp. Ther. 366(2), 314-321 (2018).

4. Trasino, S.E., Tang, X.H., Jessurun, J., et al. A retinoic acid receptor β₂ agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease. J. Mol. Med. (Berl.) 94(10), 1143-1151 (2016).