Novel phenylalanine derived diamides as Factor XIa inhibitors

[Display omitted] The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-01, Vol.26 (2), p.472-478
Main Authors: Smith, Leon M., Orwat, Michael J., Hu, Zilun, Han, Wei, Wang, Cailan, Rossi, Karen A., Gilligan, Paul J., Pabbisetty, Kumar B., Osuna, Honey, Corte, James R., Rendina, Alan R., Luettgen, Joseph M., Wong, Pancras C., Narayanan, Ranga, Harper, Timothy W., Bozarth, Jeffrey M., Crain, Earl J., Wei, Anzhi, Ramamurthy, Vidhyashankar, Morin, Paul E., Xin, Baomin, Zheng, Joanna, Seiffert, Dietmar A., Quan, Mimi L., Lam, Patrick Y.S., Wexler, Ruth R., Pinto, Donald J.P.
Format: Article
Language:English
Subjects:
Anilides - chemical synthesis
Anilides - pharmacology
Animals
Anticoagulant
aPTT
Crystallography, X-Ray
Dogs
Factor XIa
Factor XIa - antagonists & inhibitors
FXIa
Phenylalanine - analogs & derivatives
Phenylalanine - chemical synthesis
Phenylalanine - pharmacology
Rabbits
Serine protease
Structure-Activity Relationship
Thrombosis
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Summary:[Display omitted] The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.11.089