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Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Mar 26; Vol. 58 (6), pp. 2799-808. Date of Electronic Publication: 2015 Mar 12. - Publication Year :
- 2015
-
Abstract
- A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.
- Subjects :
- Blood Coagulation drug effects
Crystallography, X-Ray
Factor VIIa metabolism
Halogens chemistry
Halogens pharmacology
Heterocyclic Compounds chemistry
Heterocyclic Compounds pharmacology
Humans
Lactams metabolism
Lactams pharmacology
Models, Molecular
Molecular Docking Simulation
Drug Design
Factor VIIa antagonists & inhibitors
Serine Proteinase Inhibitors chemistry
Serine Proteinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25764119
- Full Text :
- https://doi.org/10.1021/jm501982k