Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. Issue 7 (1st April 2015)

• Record Type: Journal Article
• Authors: Pinto, Donald J.P.; Smallheer, Joanne M.; Corte, James R.; Austin, Erin J.D.; Wang, Cailan; Fang, Tianan; Smith, Leon M.; Rossi, Karen A.; Rendina, Alan R.; Bozarth, Jeffrey M.; Zhang, Ge; Wei, Anzhi; Ramamurthy, Vidhyashankar; Sheriff, Steven; Myers, Joseph E.; Morin, Paul E.; Luettgen, Joseph M.; Seiffert, Dietmar A.; Quan, Mimi L.; Wexler, Ruth R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 7(2015)
• Page Start: 1635
• Page End: 1642
• Publication Date: 2015-04-01
• Subjects: Factor XIa -- Anticoagulant -- Thrombosis -- Bioavailability -- Serine protease; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Compound2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of2 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 compound32 with FXIa K i = 6.7 nM and modest oral exposure in dogs.