Bioorganic and medicinal chemistry letters (2019)
Update date:2022-08-04
Topics:
Bozarth, Jeffrey M.
Clark, Charles G.
Corte, James R.
De Lucca, Indawati
Ewing, William R.
Fang, Tianan
Harper, Timothy
Hu, Z.
Jeon, Yoon
Lam, Patrick Y. S.
Lou, Zhen
Luettgen, Joseph M.
Myers, Joseph E.
Nirschl, David S.
Orwat, Michael J.
Pinto, Donald J. P.
Rendina, Alan
Rossi, Karen A.
Seiffert, Dietmar A.
Sheriff, Steven
Smallheer, Joanne M.
Wang, Yufeng
Wexler, Ruth R.
Wu, Yiming
Xiang, Qian
Xin, Baomin
Yang, Wu
Zheng, Joanna
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.
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