Metabolism of a potent neuroprotective hydrazide

Using a drug discovery scheme for Alzheimer’s disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J147, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J147 in human and mouse microsomes and mouse plasma. It is shown that J147 is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J147 may contribute to its biological activity in animals.

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