Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-11-19 DOI:10.1021/acs.jmedchem.4c02230

Kevin J Filipski, Luis A Martinez-Alsina, Matthew R Reese, Edelweiss Evrard, Leanne M Buzon, Kimberly O Cameron, Yuan Zhang, Karen J Coffman, James Bradow, Bethany L Kormos, Shenping Liu, John D Knafels, Parag V Sahasrabudhe, Jie Chen, Amit S Kalgutkar, Andrew J Bessire, Christine C Orozco, Amanda Balesano, Matthew A Cerny, Eliza Bollinger, Allan R Reyes, Brigitte Laforest, Amy Rosado, George Williams, Mackenzie Marshall, Kelly Tam Neale, Xian Chen, Dinesh Hirenallur-Shanthappa, John C Stansfield, John Groarke, Ruolun Qiu, Spinel Karas, Rachel J Roth Flach, William P Esler

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Abstract

Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing.

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发现首个支链酮酸脱氢酶（BDK）抑制剂临床候选药物 PF-07328948。

支链氨基酸（BCAA）代谢的负调控因子支链酮酸脱氢酶激酶（BDK 或 BCKDK）被认为可用于治疗心血管代谢疾病。PF-07328948 的出发点是潜在的特异性毒性风险，但通过对苯并噻吩核心的改造和对隐蔽口袋的发现，3-芳基取代物的效力得到了提高，最终形成了 PF-07328948，它在很大程度上不具有与蛋白质共价结合的作用。在细胞和体内啮齿动物研究中，这种 BDK 抑制剂也被证明是一种 BDK 降解剂。由于 BDK 降解作用，血浆生物标志物（包括 BCAAs 和支链酮酸 (BCKAs)）在体内降低，长期用药后药效学效应增强。该分子能改善啮齿动物模型的代谢和心衰终点。PF-07328948 是首个进行临床研究的已知选择性 BDK 候选抑制剂，1 期单次升剂量数据显示其耐受性良好，药代动力学特征与每日一次给药相称。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.