Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/αIIbβ3 dual activity and improved water solubility

Abstract In order to optimize our novel integrin α v β 3 /α IIb β 3 dual antagonists, spatial screening at the N-terminus was performed. The α v β 3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against α IIb β 3 was well maintained. The (3 S )-aminopiperidine analogue had the strongest activity against α v β 3 , and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the α v β 3 receptor were performed to confirm the SAR findings.