Accelerating GPCR Drug Discovery with Novel Macrocycles

G protein-coupled receptors (GPCRs) is a vast family of transmembrane proteins that are found primarily on the surfaces of various cell types and influencing a wide range of physiological functions. From a pharmaceutical point of view GPCRs are one of the most successful targets for therapeutic intervention spanning nearly all therapeutic areas, including the central nervous system, cardiovascular and metabolic disorders. One recent example of successful GPCR-oriented therapeutics class is GLP-1 receptor agonists that have garnered considerable attention within the medical community for their novel mechanisms of action, impressive therapeutic effectiveness and extensive potential for diabetes and obesity treatment.

GPCR-oriented macrocycles are gaining their momentum in GPCR drug discovery due to several unique characteristics:

• Rich sp3 -carbon and stereochemical scaffold diversity
• Precise spatial distribution of binding interactions
• Structural preorganization of key pharmacophores that elicit favorable receptor−ligand interactions
• Increased the desirable ADME properties such as oral bioavailability

Basic amine group

A common feature of many Class A GPCR ligands (e.g. biogenic amines) is the presence of a basic amine group. This structural motif is key to how these ligands bind within the receptor’s binding pocket. Basic nitrogen-containing macrocycles have been shown to be quite membrane permeable in certain contexts, particularly when the charge is counterbalanced by appropriately placed hydrophobic regions within the macrocycle. Therefore, at Pyxis we deliberately enriched our GPCR-oriented macrocyclic library with these favorable elements. The structural features of Class B modulators tend to mimic natural peptide ligands which often adopt an alpha-helical conformation to modulate receptors’ state. Several non-peptide synthetic macrocyclic scaffolds designed at Pyxis can replicate an alpha-helix conformation by projecting the key pharmacophoric elements into helical arrangement.

Novelty

Not only Pyxis-designed macrocycles are attractive for discovery of novel effective GPCR modulators, but also, they occupy a non-congested IP chemical space which secures a competitive advantage for drug candidate development without heavy-lifting medicinal and process chemistry.

Learn more about Pyxis Macrocycles for GPCR by reaching out our team.