作者
Lyman Smith,Michael J. Orwat,Zilun Hu,Wei Han,Cailan Wang,Karen A. Rossi,Paul J. Gilligan,Kumar Pabbisetty,Honey Osuna,James R. Corte,Alan R. Rendina,Joseph M. Luettgen,Pancras C. Wong,R. Narayanan,Timothy W. Harper,Jeffrey M. Bozarth,Earl J. Crain,Anzhi Wei,Vidhyashankar Ramamurthy,Paul E. Morin,Baomin Xin,Joanna J. Zheng,Dietmar Seiffert,Mimi L. Quan,Patrick Y.S. Lam,Ruth R. Wexler,Donald Pinto
摘要
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 = 2.8 μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).