Macrocycles are found widely in nature and several of these natural products are marketed as effective drugs with good drug-like properties. Synthetic macrocycles by contrast have been generally underexploited for drug discovery despite the opportunities they present for addressing challenging targets. IL17A has been demonstrated to be a key pro-inflammatory cytokine in human rheumatoid arthritis and psoriasis. Small molecule macrocyclic compounds (Ensemblins) have been discovered at Ensemble Therapeutics that are nanomolar inhibitors of the interaction of the IL17A cytokine with its receptor. These compounds act as inhibitors of IL17A-stimulated IL-6 production in RASF and HT29 cells, and are also anti-inflammatory in an IL17-directed murine delayed-type hypersensitivity model. Unlike the IL17 biological therapies currently in clinical development, Ensemblins can be optimized to have desirable drug-like properties including membrane permeability and oral bioavailability.