CAD-31

CAD-31 (CAD-031; CAS 2071209-49-7) is a synthetic trifluoroacetyl hydrazone (molecular weight 404.31, C18H14F6N2O2) derived from the curcumin scaffold through four generations of phenotypic optimization at the Cellular Neurobiology Laboratory of the Salk Institute for Biological Studies. The compound was selected from a library of more than 200 derivatives of the parent compound J147 on the basis of superior potency in a human embryonic stem cell-derived neural precursor cell (hNPC) neurogenesis assay and retention of broad neuroprotective activity across six cell culture models of age-associated brain toxicity [1, 2]. In assays for trophic factor withdrawal, oxidative stress (oxytosis), in vitro ischemia, extracellular and intracellular amyloid-beta toxicity, and BDNF-like neurotrophic activity, CAD-31 demonstrates EC50 values in the range of 12 to 95 nanomolar, comparable to J147 in most assays and superior in the trophic factor withdrawal model [1]. Neurogenesis markers in human neural precursor cells (nestin, Pax6, doublecortin, Ki67) are elevated 2.6- to 5.2-fold relative to J147 at matched concentrations, representing the distinctive pharmacological advance of CAD-31 within the compound series [2]. The molecular mechanism of CAD-31 converges on the AMP-activated protein kinase (AMPK) signaling cascade. CAD-31 activates AMPK by phosphorylation at threonine 172 and inhibits the downstream target acetyl-CoA carboxylase 1 (ACC1) by phosphorylation at serine 79, resulting in elevated acetyl-CoA levels, reduced free fatty acid synthesis, and increased ketone body availability in the brain [1, 6]. This metabolic reprogramming is accompanied by reductions in inflammatory markers (vascular cell adhesion molecule, receptor for advanced glycation endproducts, clusterin) and increases in synaptic proteins (drebrin, activity-regulated cytoskeleton-associated protein) in hippocampal tissue of transgenic Alzheimer's disease mice [1]. In the therapeutic APPswe/PS1deltaE9 transgenic mouse model of Alzheimer's disease, CAD-31 administered orally at approximately 10 mg/kg to symptomatic 10-month-old mice for three months rescued hippocampus-dependent memory deficits in fear conditioning, Morris water maze, and elevated plus maze paradigms to wild-type control levels [1]. In rapidly aging SAMP8 mice, CAD-31 extended median lifespan by approximately 30 percent when administered in the final quarter of life, with corresponding preservation of youthful gene, protein, and metabolite expression profiles in the brain [6]. Pharmacokinetic characterization in rats demonstrates brain penetrance with a brain-to-plasma ratio of 2.8 at eight hours after oral gavage at 20 mg/kg, and maximum brain concentrations approximately tenfold higher than the in vitro EC50 values [1]. Preclinical safety screening shows no acute toxicity at 2 g/kg, no activity in hERG, Ames, or micronucleus assays, and no inhibition of five major cytochrome P450 enzymes at concentrations more than tenfold above the effective range [1]. No formal molecular target has been identified for CAD-31; the parent compound J147 binds the alpha-F1 subunit of mitochondrial ATP synthase (ATP5A), and CAD-31 likely engages the same or a closely related target given the shared downstream AMPK activation and neuroprotective phenotype [7, 8]. CAD-31 has not entered human clinical trials. The parent compound J147 completed a Phase 1 safety study (NCT03838185), and the related compound CMS121 has received National Institutes of Health funding for Investigational New Drug studies [5]. This monograph reviews the chemistry and synthesis lineage, molecular pharmacology, preclinical pharmacokinetics, in vivo efficacy in transgenic Alzheimer's disease and accelerated-aging models, the safety profile, and a comparative assessment of five compounds in the geroneuroprotector and Alzheimer's disease therapeutic landscape against CAD-31. The compound is available as a research-grade preparation from multiple chemical suppliers; it has no approved medical indication in any jurisdiction.