78c

Compound 78c (CD38-IN-78c; CAS 1700637-55-3) is a thiazoloquinolin(on)e small molecule identified as the lead compound from a structure-activity exploration of CD38 inhibitors reported by Haffner, Bhatt, and colleagues in 2015. It is a potent, specific, reversible, and uncompetitive inhibitor of the ectoenzyme CD38 (cluster of differentiation 38), a type II transmembrane glycoprotein with NAD+ glycohydrolase, ADP-ribosyl cyclase, and cyclic ADP-ribose hydrolase activities, with half-maximal inhibitory concentration (IC50) values of 7.3 nM against human CD38 and 1.9 nM against murine CD38, and an inhibition constant (Ki) of 8.4 nM. The compound is cell-permeable, orally bioavailable in rodent species, and non-toxic at pharmacologically active doses in chronic administration studies extending to 20 months. CD38 has been identified as the principal enzyme responsible for age-related tissue NAD+ decline, a process that contributes to mitochondrial dysfunction, impaired sirtuin signaling, metabolic derangement, and the progressive physiological deterioration characteristic of aging. By inhibiting CD38-mediated degradation of NAD+ and its biosynthetic precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), compound 78c elevates tissue NAD+ levels (greater than 5-fold in liver and greater than 1.2-fold in skeletal muscle in diet-induced obese mice at a 2-hour time point) and thereby restores the activity of NAD+-dependent enzymes including sirtuins 1, 3, and 6 and poly(ADP-ribose) polymerases.

The landmark 2018 publication by Tarrago, Chini, and colleagues in Cell Metabolism demonstrated that chronic oral administration of 78c to naturally aged mice and to Cockayne syndrome progeroid mice reverses age-related NAD+ decline and improves glucose tolerance, exercise capacity, muscle function, and cardiac function. A follow-up 2022 study by Peclat and colleagues in Aging Cell extended these findings to chronological aging, reporting that 78c increases median lifespan by approximately 10 percent, extends maximal lifespan, and improves multiple healthspan parameters including treadmill endurance, grip strength, body composition, and metabolic markers in naturally aged C57BL/6 mice, with sex-dependent differences in the magnitude of benefit. Additional preclinical studies have demonstrated cardioprotection against ischemia-reperfusion injury through preservation of tetrahydrobiopterin (BH4) and endothelial nitric oxide synthase coupling; anti-inflammatory activity through suppression of NF-kappaB-dependent cytokine expression (IL-1beta, IL-6, TNF-alpha) in macrophages and microglia; therapeutic efficacy in collagen-induced arthritis through restoration of regulatory T cell populations and immune balance; and attenuation of osteoclastogenesis and inflammatory bone resorption. The compound does not cross the blood-brain barrier at appreciable concentrations but exerts systemic anti-inflammatory and metabolic effects relevant to age-related neurodegeneration through peripheral NAD+ homeostasis.

Compound 78c has not entered human clinical trials. It is supplied by multiple research chemical vendors at greater than 98 percent purity as a research tool compound. The current research state is one of strong and replicable preclinical efficacy across aging, cardiovascular, inflammatory, and metabolic disease models, with absent clinical pharmacokinetic and safety data in humans. This monograph reviews the chemistry, synthesis, and structure-activity relationships of 78c; the molecular pharmacology of CD38 inhibition and NAD+ metabolism; the preclinical pharmacokinetic profile; the preclinical efficacy data across aging, cardiovascular, inflammatory, and metabolic disease models; sourcing and quality considerations; reconstitution and handling; stack-interaction considerations with NAD+ precursors and other metabolic agents; adverse-event and safety signal from chronic animal dosing; and a comparative assessment of five alternative CD38-targeting or NAD+-elevating compounds (MK-0159, apigenin, luteolin, quercetin, and daratumumab) against 78c on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).