Synthesis of PF-6870961, a major hydroxy metabolite of the novel ghrelin receptor inverse agonist PF-5190457.

Preclinical and human studies have indicated involvement of the ghrelin system in alcohol-related behaviors illuminating the possibility of using ghrelin receptor blockers as a pharmacological intervention for alcohol use disorder (AUD). Preliminary data from a recently conducted phase 1b human study with a ghrelin receptor inverse agonist, PF-5190457 (2-(2-methylimidazo[2,1-b][1,3thiazol-6-yl)-1-{2-(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]non-7-ylethanone), provided evidence on the safety and tolerability of this compound when co-administered with alcohol. Furthermore, the study revealed important information on the biotransformation pathways for this compound and prompted the discovery and then synthesis of a newly identified major metabolite, PF-6870961 ((R)-1-(2-(5-(2-hydroxy-6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethan-1-one). The metabolite was synthesized and fully characterized through a design that enabled it to be prepared in useful quantities. The synthesis provided direct access to the recently discovered PF-6870961 and is allowing researchers to conduct additional and deeper evaluation of its in vitro and in vivo properties.