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Optimisation of a Series of Potent and Selective GR Antagonists


Glucocorticoids regulate a plethora of biological effects via their interaction with the ubiquitously
expressed glucocorticoid receptor (GR). Excessive glucocorticoid activity leads to a large number of adverse effects, including glucose intolerance and diabetes. Chronically elevated levels of the glucocorticoid hormone, cortisol, are known to cause endogenous Cushing’s syndrome.Mifepristone (Korlym™) (Figure 1), a potent GR antagonist, is approved for the treatment of Cushing’s syndrome in the US.Mifepristone is also a potent antagonist of the progesterone receptor (PR), this activity allows for its approved use as an abortifacient drug. A series of 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulphonamides (Figure 2) had previously been reported as potent and selective GR antagonists1.Our objectives in continuing optimisation of this series were to reduce hERG activity and to improve PK properties and GR potency.

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