Discovery of A‑971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P₅) Agonist for the Potential Treatment of Neurodegenerative Disorders

S1P₅ is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood–brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P₅ modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris , 2010) (<b>29</b> in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, , AAIC 2014). Herein we describe the development of a series of selective S1P₅ agonists that led to the identification of compound <b>29</b>, which is highly selective for S1P₅ and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P₅ biology, we extensively characterized <b>29</b>, including confirmation of its selectivity in pharmacodynamic assays of S1P₁ and S1P₃ function in rats. In addition, we found that <b>29</b> improves blood–brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P₅ agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood–brain barrier such as Alzheimer’s disease or multiple sclerosis