MacroFinder® molecules are non-peptidic and consist of several subunits, which can be efficiently and flexibly assembled in a modular fashion. All subunits display one or several functional groups to which substituents can be attached. In addition, subunits can also contain stereocenters. By variation of the subunits and the appended substituents, a vast and highly diverse number of MacroFinder® molecules can be designed and prepared in an automated fashion.
A multitude of therapeutically interesting pharmacophores can be displayed by subtle variation of the ring size and the substituents. These pharmacophores can be derived from known natural and synthetic ligand classes (e.g. GPCR ligands, ion channel blockers, transcription factors and others) and transferred into MacroFinder® scaffolds. Alternatively, design ideas can arise from macrocyclic natural products, PEM molecules or X-ray structures of ligands bound to a target protein. The MacroFinder® library consists currently of about 15’000 distinct MacroFinder® compounds, which are derived from various scaffolds and pharmacophore arrangements.
MacroFinder® synthesis strategy
MacroFinder® molecules are fully synthetic compounds that can be assembled in a modular fashion by high yielding organic chemistry transformations. The MacroFinder® library is produced by a robust parallel & split mix synthesis process (up to 600 cpds formats) on solid support and/or in solution. Hence, hit-to-lead and lead optimization is driven by rapid iterative cycles of design, parallel synthesis, biological testing and ADMET profiling of MacroFinder® libraries.
The synthetic process developed at Polyphor is scalable and thus gram quantities of a lead compound can be made readily available for further in vivo profiling and toxicological studies.