Role of Mechanistic Transport Studies in Lead Optimization

During the drug discovery process an average of five to ten thousand compounds are evaluated to identify the small subset of structures with appropriate properties to become a drug. A potential drug is distinguished from a potent agonist /antagonist based on multiple factors affecting safety, exposure and marketability including target selectivity, chemical stability, physical chemical properties, and drug metabolism properties. From the drug metabolism standpoint unfavorable pharmacokinetics is one of the primary barriers to overcome in drug discovery. In the case of most CNS drugs, this is further complicated by the requirement for the compound to traverse the blood-brain barrier in order for it to be efficacious. Thus, for CNS drugs, a compound must balance chemical properties conferring good CNS penetration, favorable metabolic characteristics, and good oral absorption in addition to high potency against the target activity.