Details

Autor(en) / Beteiligte

• Hu, Zilun
• Wong, Pancras C
• Gilligan, Paul J
• Han, Wei
• Pabbisetty, Kumar B
• Bozarth, Jeffrey M
• Crain, Earl J
• Harper, Timothy
• Luettgen, Joseph M
• Myers, Joseph E
• Ramamurthy, Vidhyashankar
• Rossi, Karen A
• Sheriff, Steven
• Watson, Carol A
• Wei, Anzi
• Zheng, Joanna J
• Seiffert, Dietmar A
• Wexler, Ruth R
• Quan, Mimi L

Titel

Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)‑one as the P2′ Moiety

Ist Teil von

• ACS medicinal chemistry letters, 2015-05, Vol.6 (5), p.590-595

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2015

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Structure–activity relationship optimization of phenylalanine P1′ and P2′ regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2′ group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.