- Difficult-to-drug intracellular and extracellular targets (protein-protein interactions, ion channels, GPCRs etc)
- Challenging selectivity or safety requirements (kinases, ion channels, GPCRs, enzymes, etc.)
- Oral step-down from approved biopharmaceutical or peptide (life cycle management)
- New IP in a crowded space (kinase, enzyme inhibitors, etc.)
- Circumvent lack of SAR diversity to provide alternative, promising scaffolds
Macrocycles are medium-sized molecules combining the capability to bind and modulate the function of difficult-to-drug targets typically tackled with biopharmaceuticals, and the ease of optimization and production associated with small molecule NCEs.
Macrocycles provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure;
They are semi-rigid compounds. They provide a compromise between structural pre-organization and sufficient flexibility to mould to a target surface and maximize binding (induced fit);
Medium-sized macrocycles can interact with larger protein interfaces typical for protein-protein interactions.
Macrocycles can demonstrate drug-like physicochemical and pharmacokinetic properties such as solubility, lipophilicity, metabolic stability, cell permeability and bioavailability beyond the rule of 5.
It is a rationally designed, shape-diverse collection of semi-rigid macrocycles. The design is centered around prototypical pharmacophore arrangements mimicking key naturally occurring epitopes typically involved in biological target modulation. Hits from screening the library are typically clustered in families of related compounds already providing a first limited SAR understanding.
This initial advantage is design enabled: We keep exit vector decorations constant across the various scaffolds. We have proven to be able to rapidly optimize macrocycle hit families to leads and beyond with efficient medicinal chemistry driven by structural know-how and highly efficient automated synthesis.
Polyphor offers its macrocycle library to interested parties for screening on their biological targets.
Fast “holistic” MedChem approach speeds up hit to lead optimization
Polyphor macrocycles are readily assembled in a modular fashion implemented with highly automated synthesis technologies. Rather than addressing MedChem optimization questions (SAR, ADMET etc.) in a stepwise, individual fashion, we address several medicinal chemistry aspects at once and optimize in large library arrays (300-1’000 macrocycles) per optimization round with an average synthesis time of 5-6 weeks per array. This enables a rapid gain of knowledge and structure activity understanding, ultimately shortening hit to lead time considerably and speeding up the overall drug discovery process.