The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na + /K + ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na + /K + ratio in vivo.

In one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclinical studies, we needed a strategy to enable supply of two candidates in a cost-effective and productive manner. The active pharmaceutical ingredients (APIs) were structurally complex and were initially obtained via long linear sequences resulting in time-consuming manufactures. In addition, both two candidates comprised a biaryl fragment with hindered rotation along the chiral axis. As a result, a pair of stable atropisomers was generated for each candidate. With special attention to the chromatographic challenges for the atropisomer separation and for the API purification, this article describes our initial efforts to develop synthetic routes that were amenable for multigram synthesis of our two drug candidates. In particular, the consequences of implementing a key Suzuki reaction late or early in the sequence are discussed.

We herein describe a method for palladium-catalyzed C−N cross-coupling of aryl amines and aryl halides in a biphasic reaction medium composed of 2methyltetrahydrofuran (MeTHF) and water. By effective solubilization of the inorganic base used, common challenges associated with the scalability of Buchwald− Hartwig aminations using inorganic bases were circumvented. The mildly basic nature of the reaction conditions was highlighted by the facile coupling of a base-sensitive substrate, which could be converted to the corresponding product with a high level of crude purity. The method is operationally simple and displays an improved safety and sustainability profile compared with many alternative strategies for large-scale Buchwald−Hartwig amination. Relying on a commonly available dialkylbiarylphosphine ligand, this approach was applied to three clinically relevant C−N cross-coupling reactions on the hecto-to kilogram scale.

No abstract

Enantioselective syntheses O 0031 Asymmetric Conjugate Addition of Nitroalkanes to Enones with a Chiral α-Aminophosphonate Catalyst. -(MALMGREN, M.; GRANANDER, J.; AMEDJKOUH*, M.; Tetrahedron: Asymmetry 19 (2008) 16, 1934-1940; Dep. Chem., Univ. Goeteborg, S-412 96 Goeteborg, Swed.; Eng.) -Y. Steudel 11-034