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: 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.

2-Substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic acids: Conformational prediction, synthesis, anti-thrombotic and vasodilative evaluation

“…2, E) were reported. 24 As is shown in Figure 2, the removing of a pyrrole ring from E derives 4a-q. Based on this structural correlation, the vasorelaxation assays of 4a-q were performed and the data are listed in Table 4.…”

Software and Resources for Computational Medicinal Chemistry

“…The models built with the CoMFA or CoMSIA techniques are created to identify a correlation between the molecular fields and biological activity, which can be automatically achieved with a PLS algorithm. Another 3D QSAR program that has found application in drug design is molecular field analysis from Accelrys, which is similar in its approach to CoMFA [64,65]. …”