Mitigating heterocycle metabolism in drug discovery.

■ INTRODUCTION In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. In vitro metabolism assays have become an integral part of the routine profiling of compounds made in drug discovery. The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities. Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. While several authors have reviewed these techniques for reducing metabolism, there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds. The majority of the examples that are included in this review came from searching the online open access database CHEMBL. In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field and were present in other recent reviews on drug metabolism. The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made to a compound away from the heterocycle may have influenced the metabolism. The data that we included in this review is predominantly from in vitro microsomal stability studies. However, we have included some data from bioactivation studies and in vivo PK studies to provide additional information about the overall metabolic profile. In several instances, the compound with the improved metabolic profile also became the lead compound in the paper, so we felt that including the data on the intended target was informative even though this is not a discussion point for the review. Of course, in some examples when the heterocycle was modified to improve metabolic stability, the activity at the intended biological target diminished. However, we felt that these examples of improved metabolic stability would still be of value to the reader. In the discussion below, we have organized the review by first discussing saturated heterocycles and then heteroaromatic compounds. Within each section we have organized the discussion by ring size.