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Design, Synthesis, and Biological Evaluation of Novel Potent and Selective αvβ3vβ5 Integrin Dual Inhibitors with Improved Bioavailability. Selection of the Molecular Core

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journal contribution
posted on 24.02.2005, 00:00 by Juan José Marugán, Carl Manthey, Beth Anaclerio, Lou Lafrance, Tianbao Lu, Tom Markotan, Kristi A. Leonard, Carl Crysler, Stephen Eisennagel, Malini Dasgupta, Bruce Tomczuk
A novel series of potent and selective αvβ3vβ5 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 αvβ3vβ5 dual antagonist with improved oral bioavailability.