For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. Initial fragments with high ligand efficiency, were identified in a fragment screening approach designed to target specifically the S-adenosyl-L-methionine pocket of catechol O-methyl transferase. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained.

[1] Christian Lerner, Roland Jakob-Roetne, Bernd Buettelmann, Andreas Ehler, Markus G. Rudolph and Rosa María Rodríguez Sarmiento*,  J. Med: Chem. 2016, 59, 10163-10175