11IR

CYP8B1 inhibitor compound 9

This is a non-PDB format compatible entry.

Summary for 11IR

• Entry DOI: 10.2210/pdb11ir/pdb
• Related: 11IH
• Descriptor: 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, 6-chloro-4-{(3S,4S)-3-methyl-4-[(4R)-3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carbonyl]piperidin-1-yl}quinoline-3-carbonitrile, ... (4 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 58108.91

Authors

Hruza, A.,Orth, P. (deposition date: 2026-02-26, release date: 2026-10-28)

Primary citation

McCracken, A.B.,Li, D.,Caldwell, J.P.,Lankin, C.,Tagat, J.,Khan, T.,Rao, A.,Zhang, T.,Caplen, M.A.,Verras, A.,Orth, P.,Hruza, A.,Ho, T.,Allen, S.,Elsen, N.L.,Dingley, K.,Duffy, R.,Wisniewski, T.,Murphy, B.,Castro-Perez, J.,Wong, K.,Streckfuss, E.,Liu, J.,Tong, W.,McKittrick, B.
Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease.
Acs Med.Chem.Lett., 17:2245-2250, 2026

PubMed 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 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 with substantially improved DMPK properties. Compound showed robust in vivo CYP8B1 inhibition in mice and provided the foundation for further optimization of this class of CYP8B1 inhibitors.

PubMed: 42866422
DOI: 10.1021/acsmedchemlett.6c00387

Experimental method

X-RAY DIFFRACTION (2.4 Å)