The compounds, compositions and methods provided herein antagonize, inhibit, decrease, reduce, suppress, or disrupt CD1d-mediated, iNKT cell-mediated, and/or iNKT cell TCR-mediated immune signaling. The sphingamide compounds were rationally designed based upon 3D structural considerations in relation to the structures of each of CD1d, the iNKT cell TCR, and the ternary complex CD1d-a-GalCer analog lipids-TCR. More specifically, the addition of an amide in the phytosphingosine tail of a derivative of α-GalCer led to a non-conserved binding with CD1d, a conserved binding with the iNKT cell TCR, and an antagonist-like phenotype.