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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引用次数: 0
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.
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.
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