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.

No abstract

No abstract

No abstract

Inhibitors. -Based on common structural features of non-nucleoside reverse transcriptase inhibitors, a series of quinolones is synthesized to overcome the current drug resistance. The data of SAR-studies support the important role of the cyclopropane moiety in rigidifying the molecules for optimal interactions. Quinolones (VIII) and (IX) display potent inhibitory activity against the WT virus and reveal promising activity against several NNRTI resistant mutants. -(ELLIS, D.; KUHEN, K. L.; ANACLERIO, B.; WU, B.; WOLFF, K.; YIN, H.; BURSULAYA, B.; CALDWELL, J.; KARANEWSKY, D.; HE*, Y.; Bioorg. Med.