Transaminases Provide Key Chiral Building Blocks for the Synthesis of Selective M1/M4 Agonists.

We have developed a chiral route toward the synthesis of muscarinic M4 agonists that was enabled by the biocatalytic synthesis of the key spirocyclic diamine building blocks 10 and 12. Using these bifunctional compounds we were able to optimize a synthetic sequence toward a collection of advanced intermediates for further elaboration. These advanced intermediates were then used as starting points for early medicinal chemistry and the identification of selective M1/M4 agonists.

Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo.

The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.

Entry into a new class of potent proteasome inhibitors having high antiproliferative activity by structure-based design.

Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.