Hubert Josien, Anilkumar G. Nair, Fa‐Xiang Ding, Yan Guo, Yiheng Chen, Ashwin U. Rao, J Liu, Ling Tong, Zhongxiang Sun, Michael M.‐C. Lo, Thomas J. Tucker, Mark W. Embrey, Aurash Shahripour, Chengwei Wu, Elisabetta Bianchi, Danila Branca, Jeffrey T. Kuethe, Joshua Lee, David A. Thaisrivongs, Paul G. Bulger, Xiaohong Zhu, Sookhee N. Ha, Jennifer M. Johnston, Daniel J. Klein, Peter Orth, Mee Ra Hong, Alexei V. Buevich, Qi Gao, Hratch J. Zokian, Kenneth A. Koeplinger, Rodger W. Tracy, Michael J. Hafey, Nicole Buist, Tjerk Bueters, Candice Alleyne, Alan Bass, Louis‐Charles Campeau, Douglas G. Johns, R. M. Garbaccio, Petr Váchal, Abbas Walji, Harold B. Wood
Abstract Herein, we report the discovery process of enlicitide (MK-0616, compound 18), an orally active macrocyclic peptide therapeutic against PCSK9 for LDL-C reduction. To overcome development bottlenecks in a prior lead (compound 1a) in a timely manner (sulfur oxidation liability, low solubility, azido potential manufacturing hazard, and alkene isomeric complexity), we deployed a novel scalable solution-phase modular fragment assembly (North/East/South/West/tail), which allowed us to accelerate the design-make-test-analyze (DMTA) cycle and preclinical profiling. Design solutions were quickly validated through this approach (a northern lactam staple, an N-benzylamide southern spacer, an RCM-derived cross-link in conjunction with solvent-exposed motifs to modulate solubility) and delivered compounds with low picomolar potency, improved solubility, stability, and PK from which enlicitide (MK-0616, compound 18) was selected for clinical progression. This modular strategy may act as a template to accelerate late-stage issue-driven SAR in highly engineered macrocyclic peptides.