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Design, synthesis, and biological evaluation of novel potent and selective alphavbeta3/alphavbeta5 integrin dual inhibitors with improved bioavailability. Selection of the molecular core.
Design, synthesis, and biological evaluation of novel potent and selective alphavbeta3/alphavbeta5 integrin dual inhibitors with improved bioavailability. Selection of the molecular core.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2005 Feb 24; Vol. 48 (4), pp. 926-34. - Publication Year :
- 2005
-
Abstract
- A novel series of potent and selective alpha(v)beta(3)/alpha(v)beta(5) dual( )()inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the guanidinium mimetics and the corresponding central templates. Guanidinium mimetics with enhaced rigidity (i.e., (2-pyridylamino)propoxy versus the 2-(6-methylamino-2-pyridyl)ethoxy) led to improved activity toward alpha(v)beta(3). Exemplary oral bioavailability in mice was achieved using the indole central scaffold. Although, oral bioavailability was maintained when the indole molecular core was replace with the bioisosteric benzofuran or benzothiophene ring systems, it was found to not significantly impact the integrin activity or selectivity. However, the indole series displayed the best in vivo pharmacokinetic properties. Thus, the indole series was selected for further structure-activity relationships to obtain more potent alpha(v)beta(3)/alpha(v)beta(5) dual antagonist with improved oral bioavailability.
- Subjects :
- Administration, Oral
Animals
Benzoxazoles chemistry
Benzoxazoles pharmacology
Biological Availability
Caco-2 Cells
Drug Design
Humans
Indoles chemistry
Indoles pharmacology
Mice
Permeability
Structure-Activity Relationship
Thiophenes chemistry
Thiophenes pharmacology
Benzoxazoles chemical synthesis
Indoles chemical synthesis
Integrin alphaVbeta3 antagonists & inhibitors
Integrins antagonists & inhibitors
Receptors, Vitronectin antagonists & inhibitors
Thiophenes chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 48
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15715463
- Full Text :
- https://doi.org/10.1021/jm049725u