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

Rational design, synthesis, and structure-activity relationship (SAR) exploration of tricyclic CD38 inhibitors with in vivo evaluation in mice.

“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.”

Mice used for pharmacokinetic and pharmacodynamic evaluations.

“Incremental property-based optimization of core and linker motifs generated analogues with enhanced unbound brain-to-plasma ratios in mice.”

Eight mice per group for the in vivo pharmacodynamic study.

“Oral dosing of 16 in mice (QDx4) resulted in dose-dependent increases in NAD+ concentrations as measured in brain and lung tissue samples (Figure ).”

Rigidification of the bioactive conformation via covalent tethering improved biochemical potency against mouse and human CD38.

“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.”

Compound 16 exhibited minimal to no inhibitory activity against off-target NAD+-consuming enzymes such as sirtuins and PARPs.

“Notably, compound 16 exhibited minimal to no inhibitory activity across a panel of off-target NAD+-consuming enzymes, consisting of sirtuins (SIRTs) and poly­(ADP-ribose) polymerases (PARPs).”