Drug candidates metabolic pathways

SMP-114 (licofelone) is a drug candidate for rheumatoid arthritis, currently in Phase II clinical trials (Figure 8.57). It inhibits all three of the major enzymes involved in the arachidonic acid pathway (5-LOX, COX-1, and COX-2), thereby preventing production of both leukotrienes and prostaglandins. This mode of action could therefore lead to a better tolerability than that of conventional cyclooxygenase (COX-1 and COX-2) inhibitors because of the shunt of arachidonic acid metabolism toward the production of proinflammatory leukotrienes, via 5-lipoxygenase (LOX). 

As the compound reaches the late discovery and candidate selection stage, the focus is to determine its major metabolic pathways, metabolic difference between species, and to identify potential pharmacologically active or toxic metabolites. Because of the complexity, comprehensive metabolite characterization studies have been typically conducted at this stage with radiolabeled standard. Identification of circulating metabolites is also important at this stage to explain the pharmacokinetic or the pharmacodynamic profile. An NCE may show efficacy that is inconsistent with what is predicted based upon the known concentration of the parent drug. These inconsistencies could be due to the presence of active metabolites. The knowledge of these metabolites will also dictate how the analysis of samples will be conducted in the development and clinical studies. 

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