- 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.