115458-99-6Relevant articles and documents
Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes
Staveness, Daryl,Sodano, Taylor M.,Li, Kangjun,Burnham, Elizabeth A.,Jackson, Klarissa D.,Stephenson, Corey R.J.
, p. 215 - 226 (2019)
Recent years have witnessed an increasing focus on saturated substructures within drug development as a result of the pharmacokinetic and toxicological benefits correlated with higher saturation content. However, the synthetic challenges presented by densely functionalized saturated architectures generally prohibit their evaluation. The abundance of anilines within high-throughput screening libraries is demonstrative of these competing needs. Anilines are prone to adverse metabolic processing, commonly necessitating re-engineering of a given drug lead to ameliorate CYP450 inhibition and/or glutathione adduction issues, but the ease with which these systems are prepared outweighs the toxicity risks. This article contributes to the need for aniline bioisosteres through the development of a robust, photochemical methodology that supplies 1-aminonorbornanes, saturated bicyclic ring systems that offer similar spatial occupancy to anilines while improving metabolic stability. The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO2Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1-aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp3-rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.
COMPOUNDS AND METHODS FOR TARGETED DEGRADATION OF KRAS
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Paragraph 00235, (2021/10/15)
Bifunctional compounds, which find utility as modulators of Kirsten ras sarcoma protein (KRas or KRAS), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the Von Hippel-Lindau E3 ubiquitin ligase and on the other end a moiety which binds KRas, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The heterobifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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Paragraph 00761-00762, (2019/10/29)
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
