A-971432 is an orally bioavailable, non-clastogenic, azetidinecarboxylate compound that acts as a highly potent and selective sphingosine-1-phosphate receptor 5 agonist (IC50?= 6 nM/S1P5, 362 nM/S1P1 and >10 μM/S1P3 in a radio-ligand binding assay) without affect the activity of 129 protein kinases (IC50?>10 μM). A-971432 is shown to enhance blood-brain barrier integrity and reverse lipid accumulation and age-related cognitive decline in mice in vivo with good pharmacokinetics (t1/2??= 5.7 h; Cmax?= 2,500 ng/ml; AUC = 35,000 ng.h/ml at 10 mg/kg, p.o. in CD1 mice). Likewise, oral gavage showed good plasma exposure and no sign of lymphopenia in rats (10, 30, and 100 mg/kg.
