Chapter 12: A Case History on the Challenges of Central Nervous System and Dual Pharmacology Drug Discovery

This chapter describes the case history of a drug discovery project targeting a centrally penetrant, dual serotonin/noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence, and highlights how key drug-like properties required for the discovery, and progression of a candidate molecule to clinical studies were successfully addressed. In particular, the medicinal chemistry strategies associated with balancing dual pharmacology with the required level of selectivity, BBB penetration, minimal CYP2D6 metabolism and pharmacokinetics are described. The use of a high confidence in vivo model and a bulk-sparing preclinical toxicology package to allow rapid determination of human pharmacokinetics were particularly important in the successful prosecution of this project.