A hallmark of Alzheimer’s disease (AD) is a reduction in acetylcholine levels (ACh) resulting from a loss of cholinergic neurons which contributes to cognitive impairment. 5HT4 agonists increase brain ACh levels and reverse memory deficits induced by cholinergic antagonists in behavioral studies. We recently advanced a potent, selective, brain penetrant 5HT4 partial agonist PF-04995274 into early clinical development. Unique metabolic products were present in pooled human plasma and the profile of the metabolites will be discussed. Due to the pharmacological profile of the metabolites, a directed SAR effort to shift metabolism away from the core piperidine of PF-04995274 resulted in novel analogs with orthogonal metabolic profiles.

Strategies toward optimizing the metabolism of a novel series of 5HT4 partial agonists

251st National Meeting (2016)

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