Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK),Journal of Medicinal Chemistry

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Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-07-23 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00807
Tim F. Ryder ₁ , Matthew F. Calabrese ₁ , Gregory S. Walker ₁ , Kimberly O. Cameron , Allan R. Reyes , Kris A. Borzilleri ₁ , Jake Delmore , Russell Miller , Ravi G. Kurumbail ₁ , Jessica Ward , Daniel W. Kung ₁ , Janice A. Brown ₁ , David J. Edmonds , Heather Eng ₁ , Angela C. Wolford ₁ , Amit S. Kalgutkar

Affiliation

Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1–3 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1–3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1–3 and M1–M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.

中文翻译：

6-氯-5- [4-（1-（羟基环丁基）苯基] -1 H-吲哚-3-羧酸（PF-06409577）和相关的吲哚-3-羧酸衍生物的酰基葡萄糖醛酸酯代谢物是单磷酸腺苷的直接活化剂激活的蛋白激酶（AMPK）

吲哚-3-羧酸衍生物作为人腺苷单磷酸激活蛋白激酶（AMPK）α1β1γ1亚型的直接激活剂的研究最终鉴定出PF-06409577（1），PF-06885249（2）和PF-06679142（3）作为潜在的临床候选者。化合物1 - 3主要在动物和人类通过清除葡萄糖醛酸化。在这里，我们描述了1 – 3的葡糖苷酸结合物的生物合成制备，纯化和结构表征。纯化的葡糖醛酸苷M1，M2和M3的光谱表征表明它们是酰基葡糖醛酸苷衍生物。体外药理学评估显示，所有三种酰基葡糖醛酸内酯均保留了含β1的AMPK亚型的选择性活化。在人肝细胞中用代表性的母体羧酸及其各自的酰基葡糖醛酸苷共轭物抑制从头脂肪生成，表明它们具有激活细胞AMPK的倾向。带有1 – 3和M1 – M3的AMPKα1β1γ1亚型的共结晶，为分子内研究提供了葡萄糖醛酸苷结合物激活AMPK的结构基础。

更新日期：2018-07-23

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