figshare
Browse
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

Download (1.02 MB)
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. Cox
Screening 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.

History