Utilization of triazine scaffolds as potential caspase inhibitors related to Q-VD-OPH

CHED 1327

Patrick Seymour, seymour.6@wright.edu1, William Grunwald Jr., william.grunwald@wright.edu2, Kashmira Kulkarni3, David R. Cool2, Thomas L. Brown4, and Daniel M. Ketcha, daniel.ketcha@wright.edu1. (1) Department of Chemistry, Wright State University, 3640 Col. Glenn Hwy, Dayton, OH 45435, (2) Department of Pharmacology and Toxicology, Wright State University, Department of Pharmacology and Toxicology, 3640 Colonel Glenn Highway, Dayton, 45435, (3) Department of Neuroscience, Wright State Univesity, Wright State Univesity Boonshoft School of Medicine, 3640 Col. Glenn Hwy, Dayton, 45435, (4) Department of Neuroscience, Wright State University, 3640 Col. Glenn Hwy, Dayton, OH 45435
Quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]methyl ketone (Q-VD(OMe)-OPH) is a next generation broad spectrum caspase inhibitor with potential promise as a therapeutic agent. In seeking to both reduce the peptidic features and increase the efficacy of caspase inhibitors, we have chosen to examine derivatives based upon the triazine scaffold. The typical protocol for rapid analog synthesis upon this scaffold involves the initial introduction of an aryl amine, followed by substitution at the secondary site by a more nucleophilic amine input. Finally, introduction of the third amine input usually requires extended heating. So as to avert this heating step we have elected to instead utilize the introduction of two oxygen-based nucleophiles followed by addition of the aspartyl phenoxy methyl ketone warhead portion.