Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity

• Published in: Journal of medicinal chemistry 2014-12, Vol.57 (23), p.9915-9932
• Main Authors: Hangeland, Jon J, Friends, Todd J, Rossi, Karen A, Smallheer, Joanne M, Wang, Cailan, Sun, Zhong, Corte, James R, Fang, Tianan, Wong, Pancras C, Rendina, Alan R, Barbera, Frank A, Bozarth, Jeffrey M, Luettgen, Joseph M, Watson, Carol A, Zhang, Ge, Wei, Anzhi, Ramamurthy, Vidhyashankar, Morin, Paul E, Bisacchi, Gregory S, Subramaniam, Srinath, Arunachalam, Piramanayagam, Mathur, Arvind, Seiffert, Dietmar A, Wexler, Ruth R, Quan, Mimi L
• Format: Article
• Language: English
• Subjects: Animals; Crystallography, X-Ray; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - pharmacology; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Indazoles - chemical synthesis; Indazoles - pharmacokinetics; Indazoles - pharmacology; Models, Molecular; Partial Thromboplastin Time; Rabbits; Thrombosis - prevention & control
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5010607

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 (K i = 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.