Brain-Penetrant CD38 Inhibitors Show Dose-Dependent NAD+ Increase in Mice
- CD38 is an enzyme central to NAD+ metabolism and calcium signaling in cells, and interest has grown in targeting it for neurological and psychiatric conditions.
- The authors designed a new tricyclic chemical series that binds CD38 by forming an adduct with the ADPR co-substrate, inhibiting the enzyme through an uncompetitive mechanism.
- Locking the molecules into their active shape — achieved by covalently linking a six-membered heteroaromatic core to an imidazole warhead — boosted biochemical activity against both mouse and human CD38.
- Iterative tuning of the core and linker chemistry, guided by physicochemical properties, improved how much unbound compound reached the brain relative to plasma in mice.
- The resulting lead, compound 16, raised NAD+ levels in mouse brain and lung tissue in a dose-dependent manner across an oral dosing range tested in vivo.
Uncompetitive, ADPR-adduct trapping is a nice trick — you're exploiting the product complex instead of slugging it out in a crowded NAD+ pocket, which should buy clean kinetics without fighting high cellular substrate levels. Downside: SAR now rides on substrate turnover, so simple biochemical assays get harder to interpret. Covalently locking the heteroaromatic-imidazole dihedral is a solid rigidification move, but I'd want the synthetic route in hand before calling it generalizable — tethering a warhead onto a tricyclic core usually adds steps and eats yield. The real work here is the Kp,uu grind: iterative core/linker tuning to buy brain exposure without bleeding potency, textbook CNS med-chem, nothing exotic, just disciplined execution. Given CD38's broad peripheral expression, especially on immune cells, I'd want peripheral engagement/immune liability data before this goes further — daratumumab's antibody route sidesteps that entirely by staying extracellular.
Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors ↗