Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease
Abstract CYP8B1 has been identified as a potential target for the treatment of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). CYP8B1 enzyme inhibitor 1 was discovered from a high-throughput screen of our compound collection; however, its poor metabolic stability prevented further in vivo evaluation. Leveraging structure-based drug design, metabolite identification and metabolic stability-guided DMPK optimization, and library synthesis to rapidly expand SAR, we identified compound 9 with substantially improved DMPK properties. Compound 9 showed robust in vivo CYP8B1 inhibition in mice and provided the foundation for further optimization of this class of CYP8B1 inhibitors.
Authors
- Andreas Verras (ORCID: https://orcid.org/0000-0001-5353-4784)
- Amy Bittner McCracken
- Nathaniel L. Elsen (ORCID: https://orcid.org/0000-0003-1192-7242)
- Mary Ann Caplen
- John P. Caldwell
- Brian McKittrick
- BethAnn Murphy
- Li Li (ORCID: https://orcid.org/0000-0001-5575-0894)
- Samantha Allen (ORCID: https://orcid.org/0000-0001-5986-5947)
- Weidong Tong (ORCID: https://orcid.org/0000-0003-2715-2218)
- Derun Li (ORCID: https://orcid.org/0000-0003-0512-6684)
- Ashwin Rao
- Alan Hruza (ORCID: https://orcid.org/0000-0001-8837-6368)
- Thu Ho
- Peter Orth (ORCID: https://orcid.org/0000-0002-8475-682X)
- Tanweer Khan
- Tianyuan Zhang
- Jayaram Tagat
- Jose Castro-Perez
- Claire Lankin
- Ruth Duffy
- Kenny Wong
- Thomas Wisniewski
- Eric Streckfuss
- Karen Dingley
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2026-09-16
- DOI
- https://doi.org/10.1021/acsmedchemlett.6c00387
- Primary Topic
- Pharmacogenetics and Drug Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00