Cyclic adenosine 5'-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5'-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the non-essential nature of the "southern" ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs and 8-amino¬-N9-butyl-cIDPR is comparable to the best non-covalent CD38 inhibitors to date (IC50 3.3 μM). Crystallographic analysis of the shCD38:8-amino¬-N9-butyl-cIDPR complex to a 2.05Å resolution unexpectedly reveals an N1-hydrolyzed ligand in the active site, suggesting that it is the N6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the "northern" ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38 and may aid future inhibitor design.