(W1030-06-35) Pharmacologically Active Drug Metabolites: Impact on Drug Discovery

Purpose: To evaluate the metabolism of a test article which is typically the most predominant way of the clearance of small molecule drugs from the body. Other elimination routes include urinary and/or biliary clearance of unchanged drug. Metabolism involves the conversion of a drug to more polar metabolites to help in subsequent rapid elimination. Usually, metabolites are structurally different enough from the parent molecule so that they are devoid of on-target activity. In rare instances, metabolites can retain enough structural/chemical features which allow them to have similar or better intrinsic ability to bind to the same target as its parent. In such cases it is important to consider the potential advantages and liabilities the pharmacologically active metabolites can offer.

Methods: All the data collected was quantified or identified on the API-5500 triple quadrupole or 6600 triple TOF mass spectrometers. The PK parameters were calculated utilizing Phoenix PK and PD Platform Version 8.3.

Results: Here presented is a case study in a specific neurology program, where Parent Molecule A was extensively metabolized forming two N-demethylation metabolites (Metabolite A1 and Metabolite A2). Both metabolites were identified to be potentially active. Therefore, it was important to evaluate the impact of these potentially active metabolites in vivo. The exposure of both metabolites in multiple studies were monitored. The PK exposure in mouse, rat, and cynomolgus monkeys were substantial enough to have potential impact on efficacy and safety. Furthermore, the on-target PD impact of active metabolites was confirmed in vivo in transgenic mice (mice expressing human neurology project target). Additionally, these metabolites also exhibit off-target activities against FOXM1, which is considered as a potential liability for the drug. The amount of systemically circulating Metabolite A1 in mouse (PO), rat (PO and IV), and monkey (IV) PK studies were determined to be 19.6, 18.2, 8.1, and 46.1%, respectively.

Conclusion: It is critical to perform Metabolite ID for lead compounds in early drug discovery and determine if there are any active metabolites present and calculate their circulating concentrations. Mouse PK/PD study showed 7X difference in potency between brain and blood, potentially because of circulating active metabolite which is peripherally restricted.

References: Fura A (2006) Role of pharmacologically active metabolites in drug discovery and development. Drug Discov Today 11:133–142.

Acknowledgements: Medicinal Chemistry Colleagues




Figure 2. Mouse PK/PD study dosed with 30 mg/kg of Parent Compound A

Figure 3. Rat IV/PO PK study dosed with Parent Compound A