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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.

Authors :
Marugán JJ
Manthey C
Anaclerio B
Lafrance L
Lu T
Markotan T
Leonard KA
Crysler C
Eisennagel S
Dasgupta M
Tomczuk B
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.

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