Discovery of 6-ethyl-2,4-diaminopyrimidine-based small molecule renin inhibitors

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

“…• CATALYST (Version 4.11), Accelrys Inc. ( [20][21][22][37][38][39][40], which strongly supports the notion that their in vitro bioactivities were determined by a single assay procedure. The bioactivities were expressed as the concentration of the test compound that inhibited the activity of renin by 50% (IC 50 ).…”

“…However, the fact that pharmacophore and QSAR modeling necessitates that the training compounds should have been assayed by a single bioassay procedure restricted us to certain published inhibitors (1-119, see Table A in Supplementary Materials and Fig. 2) [20][21][22][37][38][39][40]. Nevertheless, in order to assess the structural diversity of the collected compounds, and hence their aptness for pharmacophore and QSAR modeling, we calculated several diversity-related parameters for the collected list and compared them with closely related list of compounds extracted from the ZINC database (329 compounds) [53], which we used as decoys for ROC analysis (see Section 2.1.8).…”

“…We employed the HYPOGEN module from the CATALYST software package to construct numerous plausible binding hypotheses for renin inhibitors [20][21][22][37][38][39][40]. Subsequently, genetic function algorithm (GFA) and multiple linear regression (MLR) analysis were employed to search for optimal QSAR that combines highquality binding pharmacophores with other molecular descriptors and capable of explaining bioactivity variation across a collection of diverse renin inhibitors.…”

The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

“…Structural analysis of the renin-2 complex revealed that the large S2 hydrophobic pocket and the smaller hydrophobic S3 subpocket were unoccupied. Since preliminary studies to fill the S2 pocket failed 2 was first tethered by a tetrahydroisoquinoline (3) and a benzoxazinone (4) ring system which were extended by a methoxypropyl side-chain toward the S3 subpocket [54,55]. Both compounds showed substantially higher affinity relative to 2 with a particular advantage of 3 having lower IC 50 and K d as compared to that of 4.…”

“…Diaminopyrimidine-type renin inhibitors were discovered by an HTS campaign at Pfizer identifying 1 having high micromolar affinity ( Figure 6) [54].…”