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.

临床前和人体研究表明生长素释放肽系统参与酒精相关行为，阐明了使用生长素释放肽受体阻滞剂作为酒精使用障碍 (AUD) 的药物干预的可能性。最近进行的 1b 期人体研究的初步数据使用生长素释放肽受体反向激动剂 PF-5190457（2-（2-甲基咪唑 [ 2,1- b ][1,3thiazol-6-yl）-1-{2-( 1 R )-5-(6-甲基嘧啶-4-基)-2,3-二氢-1 H-inden-1-yl]-2,7-diazaspiro[3.5]non-7-ylethanone)，提供了该化合物与酒精联合给药时的安全性和耐受性的证据。此外，该研究揭示了有关该化合物生物转化途径的重要信息，并促使发现并合成了一种新鉴定的主要代谢物 PF-6870961 (( R )-1-(2-(5-(2-hydroxy-6) -methylpyrimidin-4-yl)-2,3-dihydro-1 H -inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1- b]thiazol-6-yl)ethan-1-one). 代谢物是通过设计合成和充分表征的，使其能够以有用的数量制备。该合成提供了对最近发现的 PF-6870961 的直接访问，并允许研究人员对其体外和体内特性进行额外和更深入的评估。