Conferência 4: LML134, an H3R inverse agonist for the treatment of narcolepsy

Histamine H3 receptor (H3R) inverse agonists are efficacious for the treatment of narcolepsy, but have a long duration of action. This leads to insomnia on the night following administration. Our aim was to identify a drug candidate with high efficacy (as determined by a receptor occupancy above 85%), and a fast elimination from the receptor in the brain, to avoid unwanted effects.

Yves will present the medicinal chemistry program that led to the identification of the clinical development compound LML134, and how the team solved the issues associated with brain penetration, receptor binding kinetics, hERG, phospholipidosis and a number of sometimes surprising challenges that appeared along the way. The comparison of the preclinical profile of LML134 with its phase I clinical data will show how the strategy of addressing toxicity alerts early, and optimizing receptor occupancy, allowed to reach the criteria set at the onset of this program: safety, efficacy, and a short duration of action.