| Summary: | Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the <i>N</i>1-ribosylated, Ca<sup>2+</sup>-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). <i>N</i>1-Inosine 5′-monophosphate (<i>N</i>1-IMP) is a fragment directly related to cADPR. 8-Substituted-<i>N</i>1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the <i>N</i>1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5′-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH<sub>2</sub>-<i>N</i>1-IMP is the most potent inhibitor (IC<sub>50</sub> = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach.
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