4X6M

FACTOR XIA IN COMPLEX WITH THE INHIBITOR 1-{(1S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-3-[2-(aminomethyl)-5-chlorobenzyl]urea

Summary for 4X6M

• Entry DOI: 10.2210/pdb4x6m/pdb
• Related: 4X6N 4X6O 4X6P
• Descriptor: Coagulation factor XI, light chain, 1-{(1S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-3-[2-(aminomethyl)-5-chlorobenzyl]urea, SULFATE ION, ... (5 entities in total)
• Functional Keywords: serine protease, blood coagulation factor, protein inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P03951
• Total number of polymer chains: 1
• Total formula weight: 28804.47

Authors

Wei, A. (deposition date: 2014-12-08, release date: 2015-02-18, Last modification date: 2024-10-16)

Primary citation

Pinto, D.J.,Smallheer, J.M.,Corte, J.R.,Austin, E.J.,Wang, C.,Fang, T.,Smith, L.M.,Rossi, K.A.,Rendina, A.R.,Bozarth, J.M.,Zhang, G.,Wei, A.,Ramamurthy, V.,Sheriff, S.,Myers, J.E.,Morin, P.E.,Luettgen, J.M.,Seiffert, D.A.,Quan, M.L.,Wexler, R.R.
Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.
Bioorg.Med.Chem.Lett., 25:1635-1642, 2015

PubMed Abstract: Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.

PubMed: 25728130
DOI: 10.1016/j.bmcl.2015.01.028

Experimental method

X-RAY DIFFRACTION (2.4 Å)