1. Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening.
- Author
-
Cheney DL, Bozarth JM, Metzler WJ, Morin PE, Mueller L, Newitt JA, Nirschl AH, Rendina AR, Tamura JK, Wei A, Wen X, Wurtz NR, Seiffert DA, Wexler RR, and Priestley ES
- 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
- 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.
- Published
- 2015
- Full Text
- View/download PDF