Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity

J Med Chem. 2014 Dec 11;57(23):9915-32. doi: 10.1021/jm5010607. Epub 2014 Dec 2.

Abstract

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 (Ki = 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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

Substances

  • Fibrinolytic Agents
  • Imidazoles
  • Indazoles
  • trans-N-((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)cyclohexanecarboxamide