molecules of the month

A metabolite and its parent: same target inhibition, different mechanisms. PF-6870961 is a growth hormone secretagogue receptor 1a (GHSR1a) inverse agonist biased for inhibition of 𝜷-arrestin signaling, in contrast to its parent compound, PF-5190457, an unbiased GHSR1a inverse agonist. PF-6870961 was discovered as a major metabolite of PF-5190457 by Pfizer during the analysis of sera from patients in Ph. Ib for heavy alcohol drinking (NCT02039349). Then, in preclinical rodent models and initial human studies, the metabolite was found to have an effect on food intake and craving. This case study serves as an interesting example of a metabolite with comparable potency to its parent, but acts through a different mechanism of action of 𝜷-arrestin-biased inverse agonism. Metabolite PF-6870961 more potently…