Development of a Metabolically Innocuous Aniline Isostere Enabled by Photoredox Catalysis

Abstract

Many promising drug candidates and pharmaceutical compounds fail due to idiosyncratic adverse drug reactions, often arising from the formation of reactive metabolites (RM). Among the many “structural alerts” responsible for these toxicity issues, anilines are well-known to undergo deleterious metabolic processing, yet the ease with which these systems are prepared often outweighs the risks. One common approach to ameliorate RM formation has been to replace the problematic functionality with an isostere that will not undergo adverse metabolic processing while maintaining therapeutic activity. Saturated carbocycles represent an attractive option for the isosteric replacement of anilines as they are more resistant to RM formation. the synthetic challenges presented by densely functionalized saturated architectures generally prohibit their evaluation. The overarching theme of this body of work is the development and application of new and enabling photocatalytic methods for the preparation of compounds capable of mimicking aniline motifs commonly found in drug molecules. Chapter 1 provides an overview of aniline metabolism and currently available isosteric scaffolds. Many of these reported strategies are limited in application, scope, and diversity. As a response to this problem, our group sought to employ the mild reactivity of photoredox catalysis in the synthesis of a new aniline isostere. Leveraging single electron oxidation of aminocyclopropanes, we were able to efficiently access the 1-aminonorbornane (aminoNB) scaffold, a saturated bicyclic ring system that offers similar spatial occupancy to that of anilines. Chapter 2 outlines the optimization, functional group compatibility, and scalability of this reaction platform. During the course of the initial reaction development, several unique mechanistic features were noted, and an in-depth study of the reaction mechanism is presented in Chapter 3. In agreement with experimental studies and computational analysis, C7-diastereoselectivity is controlled by a mode of 1,2-asymmetric induction hinging on an intramolecular electrostatic interaction in the transition-state of the 5-exo-trig cyclization. A discussion on the role of ZnCl2 in the reaction mechanism is included, with experimental observations supporting the theory that Lewis acids may operate in multiple capacities to benefit the efficiency of the reaction. To demonstrate the viability of the aminoNB as an aniline isostere hypothesis, a KCNQ agonist scaffold in preclinical development that has previously been shown to suffer from adverse metabolic processing was re-engineered by incorporating differentially substituted aminoNBs. Using the knowledge obtained from the methodology development and mechanistic study, a first-generation analog library is in development using a modular synthetic approach. Chapter 4 discusses these synthetic efforts and proposes future directions for a second-generation library. Collaborative efforts to assess the metabolic profile and KCNQ agonism behavior of the analogs are described in Chapter 5. Both model systems and final aminoNB analogs demonstrate enhanced metabolic stability in a standard microsomal stability assay, and preliminary metabolite identification suggests limited propensity for RM formation. KCNQ agonism activity was investigated by manual whole cell electrophysiology, and initial studies reveal promising results. Taken together, the work presented in this thesis culminates in proof-of-concept for aminoNBs to enact as metabolically innocuous aniline isosteres. Future work will focus on further optimization of the aminoNB analogs, and biological studies will incorporate a high-throughput screening platform to detect KCNQ agonism activity and selectivity. Given the ubiquity of the aniline motif, similar isosteric strategies could be applied to an array of scaffolds encompassing established drugs to preclinical leads, thereby potentially impacting a wide range of diseases.