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P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Mar 01; Vol. 21 (5), pp. 1532-5. Date of Electronic Publication: 2010 Dec 28. - Publication Year :
- 2011
-
Abstract
- Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Anticoagulants chemistry
Anticoagulants pharmacology
Binding Sites
Biological Availability
Dogs
Molecular Structure
Pyrazines chemistry
Pyrazines pharmacology
Rats
Structure-Activity Relationship
Anticoagulants chemical synthesis
Blood Coagulation Disorders drug therapy
Drug Design
Pyrazines chemical synthesis
Thrombin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 21295466
- Full Text :
- https://doi.org/10.1016/j.bmcl.2010.12.108