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Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

1,3‐'s a crowd: The facility of the AlCl3‐catalyzed Nazarov cyclization of electron‐rich aryl dienones was found to be dependent upon the substitution of the diene portion (see scheme). For α,γ‐substituted systems, pronounced 1,3‐allylic strain in the reactant is alleviated in the transition state for electrocyclization, leading to enhanced reactivity. DFT calculations support this analysis and have proven to be predictive of reactivity.

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