Ideal starting point (or entirely new direction) for your drug discovery
Could you benefit from unexplored chemical space for your target?
If you have a challenging target with a large and flexible binding site we can design new macrocycles or modify our existing ones tailoring them to your project requirements. In the process you will gain an ideal starting point for your drug discovery in an entirely new chemical space.
Why macrolide inspired macrocycles?
Macrolides are an exceptional starting point for constructing macrocycles. Although they do not follow conventional Lipinski Ro5, they are druggable and possess demonstrated clinical relevance. By creating a macrolide inspired macrocyclic library we aim to get the best of all worlds:
- Preserve favourable macrolide physical-chemical and PK properties
- Retain good oral bioavailability of macrolides
- Get higher stability than cyclic peptides
- Obtain novel IP free scaffolds
- Gain potential to hit challenging biological targets (with flat and large interaction surfaces)
- Achieve high chemical diversity through:
- Variety of ring sizes
- Number of diversification points
We know our macrolides. And we can take you from an entirely new scaffold to high quality hits. Depending on your project’s specific requirements, our chemistry can produce and our pharmacology can profile the compounds using the cascade designed to complement your own portfolio.
At the moment we are building the first generation macrolide inspired macrocyclic library consisting of novel scaffolds which can be further diversified using various chemical modifications. Fidelta’s medicinal chemistry, pharmacology
and ADME / PK
teams have a long history of working with macrolide compounds. It all started with a well-known antibiotic azithromycin (Zithromax®/Sumamed®) which was developed in our laboratories. One of our macrolide-steroide conjugates has currently finished phase II clinical trials for IBD.
In short, based on extensive experience in complex chemistry, analytics, biology and bioanalytics of macrocycles, we have the required expertise to:
- Generate different unique macrocyclic scaffolds by novel chemical transformations
- Design a library of original scaffolds based on retaining favourable properties of azithromycin (unique PK properties, solubility, permeability, high intracellular concentrations, range of activity)
- Eliminate antimicrobial activity with aim of removing this undesired property when going from non-antibacterial targets
- Optimise activity to various therapeutic targets
- Modulate physical-chemical and ADME properties
The properties of macrocycles put them between classical small molecules and biologicals. They combine the oral bioavailability and membrane permeability of small molecules with the specificity and activity of biologicals. The recent pharma interest has been sparked by evidence of macrocycles hitting interesting therapeutic targets with large and flexible binding regions (GPCRs and protein-protein complexes), whilst targets with overcrowded IP (like proteases and phosphatases) were recognised as an additional opportunity.
After years of researching small heterocyclic molecules and due to their low hit rate against challenging targets (like protein-protein complexes) the pharmaceutical industry is turning towards macrocycles for solutions. The shift is most visible through a constant increase in the number of macrocycle research papers in the last decade.