ACS Medicinal Chemistry Letters· 2026Q1
Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease
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- Q1SCImago
- 2026year
Short summary
Structure-based drug design yielded compound 9, a CYP8B1 inhibitor with improved metabolic stability and in vivo efficacy in mice, offering a promising therapeutic avenue for metabolic diseases like NAFLD and T2D.
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Key points
- CYP8B1 is a potential drug target for metabolic diseases like NAFLD and T2D.
- Initial inhibitor compound 1 had poor metabolic stability, limiting in vivo evaluation.
- Structure-based drug design and DMPK optimization led to compound 9 with improved properties.
- Compound 9 demonstrated robust in vivo CYP8B1 inhibition in mice.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. ACS Medicinal Chemistry Letters, 2026 · DOI ↗
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Field: Pharmacology (Pharmacology, Toxicology and Pharmaceutics)
PharmacologyPharmacology, Toxicology and Pharmaceutics