- 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.
Very often, penetration of membranes, which is essential for oral bioavailability or intracellular activity, represents a key hurdle for a candidate drug molecule. The unique design of our macrocycles is inspired by nature. Similar to a chameleon and, in molecular terms, similar to Cyclosporine A, Polyphor macrocycles can adapt their conformations to match the polarity of the environment (lipophilic to pass the membrane, hydrophilic to bind to the target).
Cyclosporin A, a natural product, is an inspiring orally bioavailable and cell penetrating peptidic macrocycle adapting its confirmation to the lipophilic membrane – or the polar target (Cyclophillin) environment.
Polyphor macrocycles contain this successful chameleon design principle of Cyclosporin A and thus have a high propensity to be orally bioavailable and cell penetrating. This example of a screening compound from our macrocycle library hides polar functionality in aprotic media and exposes them in protic media, resulting in an oral bioavailablity of 29%.
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.