Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors

Cluster of Differentiation 38 (CD38) plays a key role in NAD⁺ metabolism and calcium signaling, and recent reports highlight therapeutic opportunities for CD38 modulation in central nervous system (CNS) disorders. In this report, we describe the rational design, synthesis, and exploration of structure–activity relationships (SAR) for a novel and brain-penetrant series of tricyclic compounds that form an adduct with ADPR to inhibit CD38 in an uncompetitive manner. Rigidification of the bioactive conformation via covalent tethering of a 6-membered heteroaromatic core to an imidazole warhead served as the key design element that afforded improved biochemical potency against both mouse and human CD38. Incremental property-based optimization of core and linker motifs generated analogues with enhanced unbound brain-to-plasma ratios in mice. These efforts led to the discovery of brain-penetrant CD38 inhibitor 16, which was evaluated in vivo and demonstrated dose-dependent increases of NAD⁺ measured in mouse brain and lung tissue samples following oral doses ranging from 3 to 100 mg/kg.