The Discovery of GS-1291269: A Neutral Ketohexokinase (KHK) Inhibitor with an Unusual Thietane Amine Functional Group
Zachary A Kasun1, Xiaomin Liang1, Ryan D Ferrao1
1Gilead Sciences, Inc., Foster City, California 94404, United States.
Abstract:
Ketohexokinase (KHK) is the primary enzyme involved in fructose metabolism, converting fructose to fructose-1-phosphate (F1P). KHK is implicated in diseases, including metabolic-dysfunction-associated steatotic liver disease (MASLD) and diabetic kidney disease (DKD), among others. Herein, we describe the discovery of GS-1291269, a potent, neutral KHK inhibitor. GS-1291269 has pharmacokinetic parameters in preclinical species that support once-daily dosing in humans. The high potency and favorable PK profile of GS-1291269 can be attributed to the uncommon dioxo-thietane amine functional group, which avoids potential PK liabilities associated with acidic or basic molecules yet provides a hydrogen bond donor that is critical for potency. Furthermore, GS-1291269 demonstrated liver and kidney fructose-1-phosphate (F1P) reduction in a fructose challenge model in rats.
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