A-971432

A-971432 is a sphingosine-1-phosphate receptor 5 (S1P₅) agonist that is selective for S1P₅ over S1P₁ and S1P₃ (IC₅₀s = 0.006, 0.362, and >10 µM, respectively).¹ It inhibits forskolin-induced cAMP production in CHO cells expressing S1P₅ (EC₅₀ = 4.1 nM). A-971432 (1 µM) increases electrical resistance of hCMEC/D3 cells in an in vitro blood-brain barrier model, indicating enhanced barrier integrity, and attenuates blood-brain barrier leakage in an R6/2 transgenic mouse model of Huntington's disease when administered at a dose of 0.1 mg/kg.^1,2 A-971432 (0.1 mg/kg per day, i.p.) decreases the number of errors made in a horizontal ladder task and increases latency to fall in the rotarod test in R6/2 mice. It also increases spontaneous alternation in the t-maze in aged mice when administered at a dose of 0.1 mg/kg.¹

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1. Hobson, A.D., Harris, C.M., van der Kam, E.L., et al. Discovery of A-971432, an orally bioavailable selective sphingosine-1-phosphate receptor 5 (S1P₅) agonist for the potential treatment of neurodegenerative disorders. J. Med. Chem. 58(23), 9154-9170 (2015).

2. Di Pardo, A., Castaldo, S., Amico, E., et al. Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington’s disease. Hum. Mol. Genet. 27(14), 2490-2501 (2018).