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Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Oct2019, Vol. 29 Issue 19, pN.PAG-N.PAG. 1p. - Publication Year :
- 2019
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *BIOAVAILABILITY
*DRUG design
*CRYSTAL structure
*PARTIAL thromboplastin time
Subjects
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 29
- Issue :
- 19
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 138571834
- Full Text :
- https://doi.org/10.1016/j.bmcl.2019.08.008