Discovery of Octahydroindenes as PAR1 Antagonists
Sunkyung Lee1, Jong-Hwan Song1, Chul Min Park1
1Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
Abstract:
Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure-activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities on platelet activation were comparable to that of vorapaxar in a platelet rich plasma (PRP) aggregation assay. This series of compounds showed high potency and no significant cytotoxicity; however, the compounds were metabolically unstable in both human and rat liver microsomes. Current research efforts are focused on optimizing the compounds to improve metabolic stability and physicochemical properties as well as potency.
More Related Videos
07:30A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones
Published on: January 21, 2020
07:13Author Spotlight: Developing Parmodulins to Target Protease-Activated Receptors for Inflammation Control
Published on: May 24, 2024
Related Concept Videos
ortho–para-Directing Deactivators: Halogens
Drug-Receptor Interaction: Antagonist
Antagonists can be classified as competitive or noncompetitive based on their...
ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Indirect-Acting Cholinergic Agonists: Mechanism of Action
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
Antipsychotic Drugs: Typical and Atypical Agents
