Methyl (11a S )-1,2,3,5,11,11a-Hexahydro-3,3-dimethyl-1-oxo-6 H -imidazo-[3′,4′:1,2]pyridin[3,4- b ]indol-2-Substituted Acetates: Synthesis and Three-Dimensional Quantitative Structure−Activity Relationship Investigation as a Class of Novel Vasodilators
ABSTRACT To find selective inhibitor of phosphodiesterase type 5 (PDE5), the essential structure elements of clinically used drugs sildenafil, vardenafil, and tadalafil were combined and a tetracyclic parent was constructed to which in 2-positions substituted acetic acid methylesters were introduced to form 17 novel vasodilators, methyl (11aS)-1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3',4':1,2]- pyridin[3,4-b]indol-2-substituted acetates. By molecular field analysis (MFA), an equation of three-dimensional quantitative structure-activity relationship (3D QSAR) was established, which not only revealed the dependence of the in vitro vasorelaxation activities on the structures but also pointed out the way to design new lead compounds properly. Docking these novel vasodilators into the hydrophobic pocket of phosphodiesterase type 5 (PDE5) revealed that their adaptabilities to this pocket did significantly affect on their vasorelaxation activity. Actually, the docking adaptabilities of these novel vasodilators to PDE5 were consistent with the conformational requirements of them to MFA and with the crystal conformation of two representatives.
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ABSTRACT: Computer-aided drug design plays a vital role in drug discovery and development and has become an indispensable tool in the pharmaceutical industry. Computational medicinal chemists can take advantage of all kinds of software and resources in the computer-aided drug design field for the purposes of discovering and optimizing biologically active compounds. This article reviews software and other resources related to computer-aided drug design approaches, putting particular emphasis on structure-based drug design, ligand-based drug design, chemical databases and chemoinformatics tools.Future medicinal chemistry 06/2011; 3(8):1057-85. · 3.31 Impact Factor