Synthesis and Biological Evaluation of Potent Bisubstrate Inhibitors of the Enzyme Catechol O‐Methyltransferase (COMT) Lacking a Nitro Group

Inhibition of the enzyme catechol O-methyltransferase (COMT) represents a viable strategy for regulation of the catabolism of catecholamine neurotransmitters or their precursors, and is of considerable interest in the therapy of Parkinson's disease. Herein, we report the development of a new generation of potent bisubstrate inhibitors of COMT derived from nitro-substituted ligand 1 (Ki = 28 nM, Table 1), which achieve high biological activity despite the lack of a NO2 substituent on the catechol moiety. Their synthesis takes advantage of a convergent approach, in which a series of functionalized catechol intermediates is prepared (Schemes 2–7) and coupled to a common adenosine-derived allylic amine building block (Scheme 8). Biological activities of the newly synthesized inhibitors, determined by in vitro enzymatic assay and kinetic studies, clearly demonstrate that high inhibitory potency of the bisubstrate inhibitors is not correlated with the pKa of the catechol OH groups. Aromatic residues, connected to the catechol via a biaryl-type linkage, were found to maximally benefit from additional favorable hydrophobic interactions with the enzyme and thus to be preferred replacements of the NO2 group in 1. A competitive kinetic inhibition mechanism (Fig. 2) with respect to the cofactor binding site was confirmed in all cases, supporting a bisubstrate inhibition mode for inhibitors 2–19.