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鉴定LY3522348:一种高度选择性和口服有效的基托赫索基纳酶抑制剂

Timothy B Durham¹, Junliang Hao¹, Patrick Spinazze¹

¹Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States.

Journal of medicinal chemistry

|November 22, 2023

概括

一种新药,LY3522348,是一种选择性口服双重抑制人体基托赫索金酶异型C和A (hKHK-C,hKHK-A) 的抑制剂. 这种化合物在临床前研究中表现有前途,并已进入临床试验,以潜在的治疗用途.

科学领域:

药用化学医学化学
药理学药理学是指药理学的学科.
药物发现药物发现药物发现

背景情况:

凯托赫索基因酶 (KHK) 在果糖代谢中发挥作用.
抑制KHK异型C和A (hKHK-C,hKHK-A) 是一种潜在的治疗策略.
开发选择性口服KHK抑制剂是一个挑战.

研究的目的:

确定和描述一种新的,选择性的,口服双重抑制剂的hKHK-C和hKHK-A.
优化化合物以获得有利的药理动力学和安全性,适合每日口服剂量.
将已识别的临床候选人推进到人类临床试验中.

主要方法:

基于结构的药物设计被用来优化抑制剂与标蛋白的相互作用.
优化专注于改善吸收,分布,新陈代谢和安全 (ADMS) 档案.
制药动力学研究是在果糖代谢的小鼠模型中进行的.

主要成果:

临床候选物LY3522348 (化合物23) 被确定为一种高度选择性的口服双重抑制剂hKHK-C和hKHK-A.
优化努力成功地改善了化合物的类似药物的特性.
LY3522348在体内表现出强大的药理动力学反应.

结论:

LY3522348是针对KHK介导途径的有前途的临床候选者.
开发的化合物表现出有利于口服的特性和潜在的治疗应用.
进入临床试验的进步意味着这种药物发现计划的成功进展.

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Enzyme Inhibition

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.