PRIVILEGED STRUCTURES IN MEDICINAL CHEMISTRY: UNLOCKING THE PDE, GPCR, AND EPIGENETIC TARGET SPACE
Senior Vice President Medicinal Chemistry, Mercachembv, PO Box 6747, 6503 GE Nijmegen, The Netherlands
Today’s therapeutically relevant targets cluster into multimember gene families which exhibit structural and functional commonalities in molecular recognition. Thorough analysis of these shared features allows for the definition of key pharmacophoric elements that can be translated into novel small-molecule modulators of those target proteins.
We have focused our interest on the multi-member target classes of phosphodiesterases, GPCRs, and epigenetic target proteins and analyzed the relevant family-wide recognition elements that can be exploited for designing privileged structures aimed at those target families.
Multiple designs of novel privileged structures will be introduced that exhibit the negative imprint of those pharmacophoric elements, and as such qualify as molecular platforms for the generation of leads for multiple members of a respective target class. Special emphasis will be laid on the design principle of “escaping from flatland”, thus generating compounds with an increased fraction of fully saturated sp3 carbons. This usually aligns with more complex chemistry including stereogenic centers, but is addressing one of the main shortcomings within the last 20 years of medicinal chemistry, i.e. the trend of making increasingly flat molecules.
The process of designing those privileged structures with built-in 3D complexity for e.g. PDE’s with front-loaded selectivity profiles, for GPCRs with encoded cross-target synergies, and for HDACs will be presented.