PF-03882845, a non-steroidal mineralocorticoid receptor antagonist, prevents renal injury with reduced risk of hyperkalemia in an animal model of nephropathy

Abstract

The mineralocorticoid receptor (MR) antagonists PF-03882845 and eplerenone were evaluated for renal protection against aldosterone-mediated renal disease in uninephrectomized Sprague-Dawley (SD) rats maintained on a high salt diet and receiving aldosterone by osmotic mini-pump for 27 days. Serum K+ and the urinary albumin to creatinine ratio (UACR) were assessed following 14 and 27 days of treatment. Aldosterone induced renal fibrosis as evidenced by increases in UACR, collagen IV staining in kidney cortex, and expression of pro-fibrotic genes relative to sham-operated controls not receiving aldosterone. While both PF-03882845 and eplerenone elevated serum K+ levels with similar potencies, PF-03882845 was more potent than eplerenone in suppressing the rise in UACR. PF-03882845 prevented the increase in collagen IV staining at 5, 15 and 50 mg/kg BID while eplerenone was effective only at the highest dose tested (450 mg/kg BID). All doses of PF-03882845 suppressed aldosterone-induced increases in collagen IV, transforming growth factor-β 1 (Tgf-β 1), interleukin-6 (Il-6), intermolecular adhesion molecule-1 (Icam-1) and osteopontin gene expression in kidney while eplerenone was only effective at the highest dose. The therapeutic index (TI), calculated as the ratio of the EC50 for increasing serum K+ to the EC50 for UACR lowering, was 83.8 for PF-03882845 and 1.47 for eplerenone. Thus, the TI of PF-03882845 against hyperkalemia was 57-fold superior to that of eplerenone indicating that PF-03882845 may present significantly less risk for hyperkalemia compared to eplerenone.

Amiloride Is Effective in the Management of Abiraterone-Induced Mineralocorticoid Excess Syndrome without Interfering with Its Antineoplastic Activity

“…Interestingly, novel non-steroidal compounds, that, due to their chemical structure may not bind ARs, are in clinical development [13]. …”

Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study‐Heart Failure (ARTS‐HF): a randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease

“…The authors determined a therapeutic index (i.e. the ratio of EC50 for increasing serum/plasma [K + ] to the EC50 for reducing urine albumin levels) of PF‐03882845 against hyperkalaemia that was 57‐fold superior to that of eplerenone . Similarly, Kolkhof et al demonstrated that finerenone reduces functional and structural parameters of end‐organ failure more efficiently than eplerenone at equinatriuretic doses in preclinical rat disease models.…”

“…This theory is supported by two recent preclinical studies. Orena et al determined the plasma concentrations of eplerenone and the novel non‐steroidal MRA PF‐03882845 that were necessary to confer renal protection and to increase serum/plasma [K + ] in a rat kidney injury model. The authors determined a therapeutic index (i.e.…”

Third-generation Mineralocorticoid Receptor Antagonists

“…One of these, PF-3882845 (3S, 3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g] indazole-7-carboxylic acid), is orally available, potent, selective for the MR, and significantly decreased the renal pathology and loss of function in an aldosterone + salt excess model with less risk for hyperkalemia as compared to eplerenone 147, 148 . The first clinical phase I trial was terminated due to safety concerns.…”