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Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2007 Dec 01; Vol. 17 (23), pp. 6481-8. Date of Electronic Publication: 2007 Oct 01. - Publication Year :
- 2007
-
Abstract
- A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
- Subjects :
- Antithrombin III metabolism
Antithrombin III pharmacology
Caco-2 Cells
Drug Design
Humans
Indoles pharmacology
Protein Binding
Pyrazoles pharmacology
Structure-Activity Relationship
Antithrombin III chemical synthesis
Antithrombin III pharmacokinetics
Factor Xa Inhibitors
Indoles chemistry
Indoles pharmacokinetics
Pyrazoles chemical synthesis
Pyrazoles pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 17
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 17933529
- Full Text :
- https://doi.org/10.1016/j.bmcl.2007.09.091