Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.
Activated partial thromboplastin time
Anticoagulant
Bioavailability
FXIa
Factor XIa inhibitors
Thrombosis
aPTT
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
received:
23
05
2019
revised:
30
07
2019
accepted:
04
08
2019
pubmed:
26
8
2019
medline:
22
9
2020
entrez:
26
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31445854
pii: S0960-894X(19)30534-7
doi: 10.1016/j.bmcl.2019.08.008
pii:
doi:
Substances chimiques
Ligands
0
Macrocyclic Compounds
0
Serine Proteinase Inhibitors
0
Factor XIa
EC 3.4.21.27
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
126604Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.