Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-N1-Inosine 5'-Monophosphate, Analogues and Early Structure-Activity Relationship

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 N1-ribosylated, Ca2+-mobilizing, second messenger cyclic adenosine 5'-diphosphoribose (cADPR). N1-Inosine 5′-monophosphate (N1-IMP) is a fragment directly related to cADPR. 8-Substituted-N1-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. A total synthesis of the N1-IMP scaffold from adenine was designed and a small initial compound series facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5ʹ-phosphate group proved essential for useful activity, but substitution of this group with a sulfonamide bioisostere was not fruitful. 8-NH¬2-N1-IMP proved the most potent inhibitor (IC50 = 7.6 M) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery. Such truncated ligands further demonstrate the potential of our fragment approach.