4TY6

Factor XIa in complex with the inhibitor 4-{2-[(1S)-1-({[trans-4-(aminomethyl)cyclohexyl]carbonyl}amino)-2-phenylethyl]-1H-imidazol-4-yl}benzamide

Summary for 4TY6

• Entry DOI: 10.2210/pdb4ty6/pdb
• Related: 4NA7
• Descriptor: Coagulation factor XI, CYS-THR-THR-LYS-ILE-LYS-PRO, 4-{2-[(1S)-1-({[trans-4-(aminomethyl)cyclohexyl]carbonyl}amino)-2-phenylethyl]-1H-imidazol-4-yl}benzamide, ... (6 entities in total)
• Functional Keywords: hydrolase, serine protease, blood coagulation factor, protein inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P03951 P03951
• Total number of polymer chains: 2
• Total formula weight: 30797.92

Authors

Wei, A. (deposition date: 2014-07-07, release date: 2014-12-03, Last modification date: 2024-04-03)

Primary citation

Hangeland, J.J.,Friends, T.J.,Rossi, K.A.,Smallheer, J.M.,Wang, C.,Sun, Z.,Corte, J.R.,Fang, T.,Wong, P.C.,Rendina, A.R.,Barbera, F.A.,Bozarth, J.M.,Luettgen, J.M.,Watson, C.A.,Zhang, G.,Wei, A.,Ramamurthy, V.,Morin, P.E.,Bisacchi, G.S.,Subramaniam, S.,Arunachalam, P.,Mathur, A.,Seiffert, D.A.,Wexler, R.R.,Quan, M.L.
Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity.
J.Med.Chem., 57:9915-9932, 2014

PubMed Abstract: Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.

PubMed: 25405503
DOI: 10.1021/jm5010607

Experimental method

X-RAY DIFFRACTION (1.85 Å)