Jarmo Pystynen

Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol-O-methyltransferase inhibitor.

Compound 1 is an investigational, nanomolar inhibitor of catechol-O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of 1 was observed with two prodrugs, compared to that of 1, after oral treatment in rats.

Discovery and Structural Characterization of a Phospholamban-Binding Cyclic Peptide and Design of Novel Inhibitors of Phospholamban

The interplay between cardiac sarcoplasmic Ca2+ATPase and phospholamban is a key regulating factor of contraction and relaxation in the cardiac muscle. In heart failure, aberrations in the inhibition of sarcoplasmic Ca2+ATPase by phospholamban are associated with anomalies in cardiac functions. In experimental heart failure models, modulation of the interaction between these two proteins has been shown to be a potential therapeutic approach. The aim of our research was to find molecules able to interfere with the inhibitory activity of phospholamban on sarcoplasmic Ca2+ATPase. For this purpose, a portion of phospholamban was synthesized and used as target for a phage‐display peptide library screening. The cyclic peptide C‐Y‐W‐E‐L‐E‐W‐L‐P‐C‐A was found to bind to phospholamban (1–36) with high specificity. Its functional activity was tested in Ca2+uptake assays utilizing preparations from cardiac sarcoplasmic reticulum. By synthesizing and testing a series of alanine point‐mutated cyclic peptides, we identified which amino acid was important for the inhibition of the phospholamban function. The structures of active and inactive alanine‐mutated cyclic peptides, and of phospholamban (1–36), were determined by NMR. This structure–activity analysis allowed building a model of phospholamban –cyclic peptide complex. Thereafter, a simple pharmacophore was defined and used for the design of small molecules. Finally, examples of such molecules were synthesized and characterized as phospholamban inhibitors.