Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR
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.
Authors
- Qi Gao (ORCID: https://orcid.org/0000-0003-0052-3621)
- Hubert Josien (ORCID: https://orcid.org/0000-0002-6072-7258)
- Thomas J. Tucker (ORCID: https://orcid.org/0000-0001-5616-0802)
- Hratch J. Zokian
- Jeffrey T. Kuethe (ORCID: https://orcid.org/0000-0001-8955-6010)
- Fa‐Xiang Ding
- Ashwin U. Rao
- Xiaohong Zhu (ORCID: https://orcid.org/0000-0003-3364-258X)
- Louis‐Charles Campeau (ORCID: https://orcid.org/0000-0002-2373-802X)
- Paul G. Bulger (ORCID: https://orcid.org/0009-0008-0474-8485)
- Danila Branca (ORCID: https://orcid.org/0000-0002-6745-597X)
- Petr Váchal (ORCID: https://orcid.org/0000-0002-4101-8421)
- Mark W. Embrey
- Zhongxiang Sun (ORCID: https://orcid.org/0000-0002-0176-581X)
- Daniel J. Klein (ORCID: https://orcid.org/0000-0002-3533-3273)
- Candice Alleyne
- R. M. Garbaccio (ORCID: https://orcid.org/0000-0003-2240-3380)
- Ling Tong (ORCID: https://orcid.org/0000-0003-3302-8184)
- Douglas G. Johns (ORCID: https://orcid.org/0000-0002-8726-8514)
- Anilkumar G. Nair
- Elisabetta Bianchi (ORCID: https://orcid.org/0000-0002-5302-6912)
- Alexei V. Buevich (ORCID: https://orcid.org/0000-0002-5968-9151)
- Michael J. Hafey
- J Liu
- Mee Ra Hong (ORCID: https://orcid.org/0000-0002-2381-7684)
- David A. Thaisrivongs (ORCID: https://orcid.org/0000-0002-0387-8885)
- Chengwei Wu
- Yiheng Chen (ORCID: https://orcid.org/0000-0002-7662-9441)
- Harold B. Wood (ORCID: https://orcid.org/0000-0002-8281-0159)
- Kenneth A. Koeplinger
- Michael M.‐C. Lo
- Alan Bass
- Joshua Lee (ORCID: https://orcid.org/0009-0000-7581-5261)
- Peter Orth (ORCID: https://orcid.org/0000-0002-8475-682X)
- Jennifer M. Johnston
- Aurash Shahripour
- Tjerk Bueters
- Sookhee N. Ha
- Nicole Buist
- Rodger W. Tracy
- Abbas Walji
- Yan Guo
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Bioanalytica (Switzerland) (CH)
- Discovery Place (US)
- Quantitative BioSciences (US)
- Peptide Protein Research (United Kingdom) (GB)
- Protein Technologies (United Kingdom) (GB)
- Lead Discovery Center (Germany) (DE)
- Institute of Computational Modeling (RU)
- Drug Safety Research Unit (GB)
- IRBM Science Park (IT)
- The Medical Device (United Kingdom) (GB)
- Center for Discovery (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00463
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00