posted on 2023-01-10, 07:04authored byMark E. Layton, Jeffrey C. Kern, Timothy J. Hartingh, William D. Shipe, Izzat Raheem, Monika Kandebo, Robert P. Hayes, Sarah Huszar, Donnie Eddins, Bennett Ma, Joy Fuerst, Gordon K. Wollenberg, Jing Li, Jeff Fritzen, Georgia B. McGaughey, Jason M. Uslaner, Sean M. Smith, Paul J. Coleman, Christopher D. Cox
PDE10A is an important regulator of striatal signaling
that, when
inhibited, can normalize dysfunctional activity. Given the involvement
of dysfunctional striatal activity with schizophrenia, PDE10A inhibition
represents a potentially novel means for its treatment. With the goal
of developing PDE10A inhibitors, early optimization of a fragment
hit through rational design led to a series of potent pyrimidine PDE10A
inhibitors that required further improvements in physicochemical properties,
off-target activities, and pharmacokinetics. Herein we describe the
discovery of an isomeric pyrimidine series that addresses the liabilities
seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development
for the treatment of schizophrenia.