February 25, 2013
These selective aldosterone synthase inhibitors may lead to new drugs for kidney disease. M. G. Bell and co-inventors report pyrazole derivatives, represented by general formula 1, that act as aldosterone synthase inhibitors and may lead to new treatments for kidney disease.
Aldosterone synthase is the rate-limiting enzyme in the biosynthesis of aldosterone, a steroid hormone of the mineralocorticoid family that plays a role in sodium retention. Elevated levels of plasma aldosterone are implicated in progressive renal disease, which leads to chronic kidney disease. Animal models of kidney disease show that aldosterone synthase inhibitors are useful for treating kidney disease.
Current aldosterone synthase inhibitors are not specific to aldosterone but can also inhibit the production of cortisol, testosterone, and estradiol. Specificity for aldosterone synthase is a challenge. The compounds represented by formula 1 show good selectivity for aldosterone synthase inhibition and potentially may be used for treating chronic kidney disease and diabetic nephropathy.
The inventors describe 67 examples of formula 1 and report biological data for examples 2 and 3. They used the following assays:
- aldosterone synthase inhibitor assay,
- inhibition of aldosterone synthase in rats,
- cortisol inhibition assay,
- testosterone and estradiol production assay,
- cynomolgus monkey aldosterone inhibition assay, and
- cynomolgus monkey cortisol inhibition assay.
Data in the table are from the aldosterone synthase inhibitor assay (hcyp11B2 cells) and the testosterone and estradiol production assay.
(Eli Lilly [Indianapolis] WIPO Publication 2012173849, Dec. 20, 2012; Ahmed F. Abdel-Magid)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.