Statistical molecular design, parallel synthesis, and biological evaluation of a library of thrombin inhibitors

A library of thrombin inhibitors has been designed using statistical molecu lar design. An aromatic scaffold was used, with three varied positions corr esponding to three pockets at the active site of thrombin (the S-, P-, and D-pockets). The selection was performed in the building block space, and pr eviously acquired data were included in the design procedure. The design re sulted in six, four, and six building blocks for the first (S), second (P), and third (D) pockets, respectively. A second round of selection applied t o the combined selected building blocks resulted in a subset of 18 compound s. The selected library was synthesized in parallel and biologically evalua ted. The compounds were analyzed with respect to their inhibition (pIC(50)) of thrombin; membrane permeability, estimated by migration behavior in mic ellar media (CE log k') and pK(a); and specificity with respect to inhibiti on (K-i) of trypsin. Multivariate QSAR studies of the responses yielded val uable results and information that could only be found using statistical mo lecular design in combination with multivariate analysis.