5QQO

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(5E,8S)-8-[(6R)-6-(3-chlorophenyl)-2-oxo-1,3-oxazinan-3-yl]-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate

Summary for 5QQO

• Entry DOI: 10.2210/pdb5qqo/pdb
• Group deposition: FXIa (G_1002075)
• Descriptor: Coagulation factor XI, MET-ASP-ASP-ASP-ASP-LYS-MET-ASP-ASN-GLU-CYS-THR-THR-LYS-ILE-LYS-PRO-ARG, methyl [(5E,8S)-8-[(6R)-6-(3-chlorophenyl)-2-oxo-1,3-oxazinan-3-yl]-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate, ... (6 entities in total)
• Functional Keywords: hydrolase, serine protease, blood coagulation factor, protein inhibitor complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 31150.64

Authors

Sheriff, S. (deposition date: 2019-05-20, release date: 2019-09-18, Last modification date: 2024-10-23)

Primary citation

Clark, C.G.,Rossi, K.A.,Corte, J.R.,Fang, T.,Smallheer, J.M.,De Lucca, I.,Nirschl, D.S.,Orwat, M.J.,Pinto, D.J.P.,Hu, Z.,Wang, Y.,Yang, W.,Jeon, Y.,Ewing, W.R.,Myers Jr., J.E.,Sheriff, S.,Lou, Z.,Bozarth, J.M.,Wu, Y.,Rendina, A.,Harper, T.,Zheng, J.,Xin, B.,Xiang, Q.,Luettgen, J.M.,Seiffert, D.A.,Wexler, R.R.,Lam, P.Y.S.
Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.
Bioorg.Med.Chem.Lett., 29:126604-126604, 2019

PubMed Abstract: This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

PubMed: 31445854
DOI: 10.1016/j.bmcl.2019.08.008

Experimental method

X-RAY DIFFRACTION (2 Å)