Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1635-42. doi: 10.1016/j.bmcl.2015.01.028. Epub 2015 Feb 4.


Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.

Keywords: Anticoagulant; Bioavailability; Factor XIa; Serine protease; Thrombosis.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Factor XIa / antagonists & inhibitors*
  • Factor XIa / drug effects
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Indazoles
  • Factor XIa