作者
Timothy B. Durham,Junliang Hao,Patrick G. Spinazzé,Douglas R. Stack,John E. Toth,Steven Massey,Curren T. Mbofana,Rich D. Johnston,Jayana P. Lineswala,Aaron D. Wrobleski,José M. Mı́nguez,Carlos Pérez,Daryl L. Smith,Jason Lamar,Rebecca Leon,Christopher M Corkins,Jim D. Durbin,Frances Tung,Sherry Guo,Ryan J. Linder,Nathan Yumibe,Wei Wang,James G. MacKrell,Meghan P. Antonellis,Bethany Mascaro
摘要
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.