DUN41875

DUN41875 is an inhibitor of stearyol-CoA desaturase 1 (SCD1; IC₅₀ = 11.8 nM for the rat enzyme).¹ It increases tetramerization of soluble α-synuclein and reduces mutant α-synuclein incorporation into tetramers in BE(2)-M17 neuroblastoma cells expressing a mutant α-synuclein containing three glutamate-to-lysine substitutions at positions 35, 46, and 61 (3K) when used at concentrations of 0.01, 0.1, and 1 µM.² DUN41875 (10 or 30 mg/kg) reduces the plasma ratio of oleic acid to stearic acid in rats fed a low essential fatty acid diet.¹ It reduces the time to turn and the number of falls in the pole test, increases time to fall from the rotarod, and improves endurance in the hanging wire test in the 3K-3798 transgenic mouse model of Parkinson's disease when administered in the drinking water at a concentration of 1.9% (v/v).² DUN41875 reduces cortex somatic aggregates of phosphorylated α-synuclein and cortex levels of lysosome-associated membrane protein 1 (LAMP-1), also known as CD107a, in the brains from the same mice.

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1. Atkinson, K.A., Beretta, E.E., Brown, J.A., et al. N-Benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors. Bioorg. Med. Chem. Lett. 21(6), 1621-1625 (2011).

2. Nuber, S., Nam, A.Y., Rajsombath, M.M., et al. A stearoyl-coenzyme A desaturase inhibitor prevents multiple Parkinson disease phenotypes in α-synuclein mice. Ann. Neurol. 89(1), 74-90 (2021).