In 2012 we were asked to develop a Me-Better for a compound currently in Clinical Phase III. The product was developed for a specific indication related to cardiovascular diseases.

The project was a challenge because two key issues. First, the high potency of the compound (less than 10 nM). Second, compounds should be assayed not only for activity, but also to obtain some ADME data. This meant GalChimia was in charge of outsourcing the corresponding in vitro and in vivo assays to specialized third parties.

Two design strategies were considered. The first one was virtual screening. In collaboration with an expert partner, the target was modeled and a focused library was designed taking into account some critical characteristics of the reference compound. The second strategy was based on a classical, rational design, using no software but our expertise and experience in medicinal chemistry. We evaluated the molecule, the existing IP, potential changes, the feasibility of the synthetic routes and finally we generated a list of new chemical entities.

The second approach was the most successful. We obtained several analogues for which we designed and optimized the route of synthesis, with an average of 10 chemical steps. The molecules were tested using an in vitro assay to evaluate their potency on the target. Through several cycles of synthesis and optimization, the first obtained potencies at microM range were increased up to reach IC50 values of less than 10nM, really near the corrected potency of the reference compound in our primary assay. The most successful compounds were then tested to obtain preliminary ADME data and further optimized.

During all the work, we reported the project advances to our customer, who validated each cycle and gave us his approval for the next steps.