6W50

FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((10R,14S)- 14-(4-(3-CHLORO-2,6-DIFLUOROPHENYL)-6-OXO-3,6-DIHYDRO- 1(2H)-PYRIDINYL)-10-METHYL-9-OXO-8,16- DIAZATRICYCLO[13.3.1.0~2,7~]NONADECA-1(19),2,4,6,15,17- HEXAEN-5-YL)CARBAMATE

Summary for 6W50

• Entry DOI: 10.2210/pdb6w50/pdb
• Descriptor: Coagulation factor XI, methyl ((10R,14S)-14-(4-(3-chloro-2,6-difluorophenyl)-6-oxo-3,6-dihydro- 1(2h)-pyridinyl)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0~2,7~]nonadeca- 1(19),2,4,6,15,17-hexaen-5-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: 29132.32

Authors

Sheriff, S. (deposition date: 2020-03-12, release date: 2020-06-10, Last modification date: 2024-10-23)

Primary citation

Yang, W.,Wang, Y.,Lai, A.,Clark, C.G.,Corte, J.R.,Fang, T.,Gilligan, P.J.,Jeon, Y.,Pabbisetty, K.B.,Rampulla, R.A.,Mathur, A.,Kaspady, M.,Neithnadka, P.R.,Arumugam, A.,Raju, S.,Rossi, K.A.,Myers Jr., J.E.,Sheriff, S.,Lou, Z.,Zheng, J.J.,Chacko, S.A.,Bozarth, J.M.,Wu, Y.,Crain, E.J.,Wong, P.C.,Seiffert, D.A.,Luettgen, J.M.,Lam, P.Y.S.,Wexler, R.R.,Ewing, W.R.
Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.
J.Med.Chem., 63:7226-7242, 2020

PubMed Abstract: Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound , a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

PubMed: 32456431
DOI: 10.1021/acs.jmedchem.0c00464

Experimental method

X-RAY DIFFRACTION (1.95 Å)