Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P(5)) Agonist for the Potential Treatment of Neurodegenerative Disorders

摘要

S1P(5) is one of S 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 S1P(5) modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., AAIC 2014). Herein we describe the development of a series of selective S1P(5) agonists that led to the identification of compound 29, which is highly selective for S1P(5) and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P(5) biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P(1). and S1P(3) function in rats. In addition, we found that 29 improves blood brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P(5) 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.