Sphingosine-1-phosphate (S1P) plays an important role in angiogenesis by stimulating DNA synthesis, chemotactic motility, and early blood vessel formation. Accordingly, the S1P signaling pathway is an attractive target for novel anti-angiogenic therapeutics. Here, we describe a small synthetic derivative of SIP that acts as an anti-angiogenic agent. We found that the S1P derivative NHOBTD [N-((2.5,3R)-3-hydroxy-1-morpholino-4-(3-octylphenyl)butan-2-yl)tetradecanamide] suppressed SIP-induced invasion and tube formation by human umbilical vein endothelial cells. NHOBTD also suppressed SIP signaling, as seen by destabilization of hypoxia inducible factor-1 alpha (HIF-1 alpha) and secretion of VEGF, a transcriptional target of HIF-1 alpha. Moreover, NHOBTD profoundly blocked endogenous neovascularization of the chick embryo chorioallantoic membrane, without rupturing any existing vessels. Together, these results demonstrate that NHOBTD is a new anti-angiogenic molecule that is capable of perturbing SIP signaling, and provides the basis for developing new anti-angiogenic drugs. (C) 2011 Elsevier Inc. All rights reserved.