jm049725u_si_001.pdf (372.7 kB)
Design, Synthesis, and Biological Evaluation of Novel Potent and Selective αvβ3/αvβ5 Integrin Dual Inhibitors with Improved Bioavailability. Selection of the Molecular Core
journal contribution
posted on 2005-02-24, 00:00 authored by Juan José Marugán, Carl Manthey, Beth Anaclerio, Lou Lafrance, Tianbao Lu, Tom Markotan, Kristi A. Leonard, Carl Crysler, Stephen Eisennagel, Malini Dasgupta, Bruce TomczukA novel series of potent and selective αvβ3/αvβ5 dualinhibitors 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 αvβ3. 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 αvβ3/αvβ5 dual antagonist with improved oral bioavailability.