Structure-Based Design, Synthesis, and Memapsin 2 (BACE) Inhibitory Activity of Carbocyclic and Heterocyclic Peptidomimetics
Stephen Hanessian, Hongying Yun, Yihua Hou, Gaoqiang Yang, Malken Bayrakdarian, Éric Therrien, Nicolas Moitessier, Silvio P. Roggo, Siem J. Veenstra, Marina Tintelnot‐Blomley, Jean‐Michel Rondeau, Christian Ostermeier, André Strauss, Paul Ramage, Paolo Paganetti, Ulf Peter Neumann, Claudia Betschart · Journal of Medicinal Chemistry · 2005
Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.