jm5b00983_si_001.pdf (1.02 MB)
Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis
journal contribution
posted on 2015-10-08, 00:00 authored by William D. Shipe, Steven
S. Sharik, James C. Barrow, Georgia
B. McGaughey, Cory R. Theberge, Jason M. Uslaner, Youwei Yan, John J. Renger, Sean M. Smith, Paul
J. Coleman, Christopher D. CoxScreening of a fragment library for
PDE10A inhibitors identified
a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog
followed by iterative parallel synthesis guided by X-ray cocrystal
structures resulted in rapid potency improvements with minimal loss
of ligand efficiency. Compound 15h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity
over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity
after ip dosing.