5QTT

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(3R,7S)-7-{[5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carbonyl]amino}-3-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecin-15-yl]carbamate

Summary for 5QTT

• Entry DOI: 10.2210/pdb5qtt/pdb
• Group deposition: FXIa (G_1002107)
• Descriptor: Coagulation factor XI, methyl [(3R,7S)-7-{[5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carbonyl]amino}-3-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecin-15-yl]carbamate, SULFATE ION, ... (5 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)
• Total number of polymer chains: 1
• Total formula weight: 28985.20

Authors

Sheriff, S. (deposition date: 2019-10-16, release date: 2019-12-25, Last modification date: 2024-10-16)

Primary citation

Corte, J.R.,Pinto, D.J.P.,Fang, T.,Osuna, H.,Yang, W.,Wang, Y.,Lai, A.,Clark, C.,Sun, J.H.,Rampulla, R.A.,Mathur, A.,Kaspady, M.,Neithnadka, P.R.,Li, Y.X.,Rossi, K.A.,Myers, J.E.,Sheriff, S.,Lou, Z.,Harper, T.W.,Huang, C.S.,Zheng, J.J.,Bozarth, J.M.,Wu, Y.,Wong, P.C.,Crain, E.,Seiffert, D.A.,Luettgen, J.M.,Lam, P.,Wexler, R.R.,Ewing, W.R.
Potent, Orally Bioavailable and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.
J.Med.Chem., 63:784-803, 2019

PubMed Abstract: Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle , possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.

PubMed: 31833761
DOI: 10.1021/acs.jmedchem.9b01768

Experimental method

X-RAY DIFFRACTION (2.23 Å)