Synthesis of dipeptide secondary structure mimetics

Abstract

Masakatsu Eguchi, Hwa-Ok Kim, Benjamin S. Gardner, P. Douglas Boatman, Min S. Lee, Hiroshi Nakanishi and Michael Kahn Molecumetics Ltd., 2023 120th Ave. N.E., Suite 400, Bellevue, WA 98005, USA and Department of Pathobiology, University of Washington, Seattle, WA, 98195, USA Secondary structures in proteins and peptides play an important role in biological recognition systems. In principle, conformationally restricted mimetics of such bioactive local structures can enhance the activity of bioactive molecules. Our previous studies [1] showed that a 3-benzyl 6,5-bicyclic dipeptide mimetic for DPhe-Pro coupled with an Arg moiety (MOL-098) afforded effective thrombin inhibitory activity X-ray co-crystal structural analysis of MOL-098 with human revealed that the potent inhibitory activity was due to the extended strand structure of MOL-098 interacting with the backbone structure of the thrombin active site, and the benzyl group at the P3 position of the inhibitor interacting favorably through a hydrophobic aromatic interaction with of thrombin. In this study, we have designed a conformationally constrained analogue of the 3-benzyl 6,5-bicyclic dipeptide, (3R and 3S, 6S, 9S)-3-(t-butyoxycarbony)amino-3-benzyl-l-aza[4.3.0]nonan-2-one-9-carboxylic acid (1, 2), and developed efficient syntheses of these templates.