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Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2007 Jan 01; Vol. 15 (1), pp. 160-73. Date of Electronic Publication: 2006 Oct 04. - Publication Year :
- 2007
-
Abstract
- We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.
- Subjects :
- Administration, Oral
Animals
Binding Sites
Biphenyl Compounds chemistry
Blood Coagulation Factor Inhibitors chemistry
Blood Coagulation Factor Inhibitors pharmacology
Drug Design
Drug Evaluation, Preclinical
Humans
Hydrogen Bonding
Ligands
Lipoproteins chemistry
Lipoproteins pharmacology
Macaca fascicularis
Male
Methylamines chemistry
Mice
Mice, Inbred ICR
Models, Molecular
Molecular Structure
Protein Structure, Secondary
Sensitivity and Specificity
Stereoisomerism
Structure-Activity Relationship
Biphenyl Compounds chemical synthesis
Biphenyl Compounds pharmacology
Blood Coagulation Factor Inhibitors chemical synthesis
Factor VIIa antagonists & inhibitors
Lipoproteins chemical synthesis
Methylamines chemical synthesis
Methylamines pharmacology
Thromboplastin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17064913
- Full Text :
- https://doi.org/10.1016/j.bmc.2006.09.071