A Covalent Binding Mode of a Pyrazole‐Based CD38 Inhibitor

Abstract Brain concentrations of nicotinamide adenine dinucleotide (NAD + ), an important cellular co‐factor, tend to decrease with age and in neurodegeneration. As the NADase cluster of differentiation 38 (CD38) significantly contributes to NAD + consumption, we reasoned that CD38 inhibition may be of therapeutic value for CNS disorders. The new pyrazole compound was designed based on a known CD38 inhibitor and showed good inhibitory potency. Several attempts to co‐crystallise this pyrazole with CD38 and cyclic adenosine diphosphate ribose (cADPR) culminated in a high‐resolution X‐ray structure, in which the pyrazolyl group in the new compound formed a covalent bond with one of the ribosyl units of cADPR. This reaction proceeded under retention of configuration and resulted in a neutral ribosyl‐pyrazole conjugate that is embedded within the active site of the enzyme. An analysis of this structural complex gave rise to design principles that enabled the preparation of more potent CD38 inhibitors with drug‐like properties.