1区 · 医学
Article
作者: Antonellis, Meghan ; Lamar, Jason ; Spinazze, Patrick ; Durham, Timothy B ; Yumibe, Nathan ; Leon, Rebecca ; Wrobleski, Aaron ; Linder, Ryan J ; Mínguez, Jose Miguel ; Lineswala, Jayana P ; Massey, Steven ; Guo, Sherry ; Johnston, Richard D ; Tung, Frances ; MacKrell, James ; Perez, Carlos ; Hao, Junliang ; Smith, Daryl L ; Toth, James L ; Corkins, Christopher ; Durbin, Jim ; Wang, Wei ; Mbofana, Curren T ; Stack, Douglas R ; Mascaro, Bethany
The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.