Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 7, Pages 2131-2150Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2005.10.055
Keywords
integrin alpha(v)beta(3) antagonist; integrin alpha(IIb)beta(3) antagonist; acute ischemic disease; 3-aminopiperidine derivatives
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In order to optimize our novel integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta(3) antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta(3) was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta(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 alpha(v)beta(3) receptor were performed to confirm the SAR findings. (c) 2005 Elsevier Ltd. All rights reserved.
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