Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 3, Pages 972-986Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01196
Keywords
-
Categories
Funding
- National Major Scientific and Technological Special Project for Significant New Drugs Development during the Twelfth Five-Year Plan Period from the Chinese Ministry of Science and Technology [2013ZX0950910]
Ask authors/readers for more resources
On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNF alpha)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available