- Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
- Axten, Jeffrey M.,Romeril, Stuart P.,Shu, Arthur,Ralph, Jeffrey,Medina, Jesus R.,Feng, Yanhong,Li, William Hoi Hong,Grant, Seth W.,Heerding, Dirk A.,Minthorn, Elisabeth,Mencken, Thomas,Gaul, Nathan,Goetz, Aaron,Stanley, Thomas,Hassell, Annie M.,Gampe, Robert T.,Atkins, Charity,Kumar, Rakesh
supporting information
p. 964 - 968
(2013/10/22)
- CHEMICAL COMPOUNDS
The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer?s disease, stroke, Type 1 diabetes Parkinson disease, Huntington?s disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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(2011/10/13)
