Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability. Issue 19 (1st October 2019)

• Record Type: Journal Article
• Authors: Clark, Charles G.; Rossi, Karen A.; Corte, James R.; Fang, Tianan; Smallheer, Joanne M.; De Lucca, Indawati; Nirschl, David S.; Orwat, Michael J.; Pinto, Donald J.P.; Hu, Zilun; Wang, Yufeng; Yang, Wu; Jeon, Yoon; Ewing, William R.; Myers, Joseph E.; Sheriff, Steven; Lou, Zhen; Bozarth, Jeffrey M.; Wu, Yiming; Rendina, Alan; Harper, Timothy; Zheng, Joanna; Xin, Baomin; Xiang, Qian; Luettgen, Joseph M.; Seiffert, Dietmar A.; Wexler, Ruth R.; Lam, Patrick Y.S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 19(2019)
• Publication Date: 2019-10-01
• Subjects: Factor XIa inhibitors -- FXIa -- Activated partial thromboplastin time -- aPTT -- Thrombosis -- Anticoagulant -- Bioavailability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.08.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9 . This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9 . These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.