Abstract: SA-PO1067

MT-3995, a Novel Non-Steroidal Mineralocorticoid Receptor Antagonist, Has Pharmacological Profiles Differentiated from Eplerenone and Spironolactone

Session Information

Category: Hypertension

  • 1101 Hypertension: Basic and Experimental - Neural and Inflammatory Mechanisms

Authors

  • Kikkawa, Kohei, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Watanabe, Yoshinori, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Nishio, Masashi, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Katoh, Makoto, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
  • Shirata, Naritoshi, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Takakuwa, Misae, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Nishi, Akito, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Iguchi, Taku, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Munakata, Hitomi, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Ikeda, Tomoko, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Koyama, Naomi, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
  • Shimizu, Hidetoshi, Mitsubishi Tanabe Pharma Corporation, Toda, Japan
Background

MR antagonists such as eplerenone (Epl) and spironolactone (Spi) improve outcomes in patients with heart failure. However, their use is limited because of steroid-related adverse effects and hyperkalemia risk. MT-3995 is a novel non-steroidal MR antagonist, and the clinical studies are ongoing in patients with diabetic nephropathy (P2b). This study was planned to clarify the pharmacological profiles of MT-3995, comparing with Epl and Spi.

Methods

MR selectivity was evaluated in steroid receptor binding assays. The effect on transcriptional activity was evaluated in cultured CHO cells expressing “Gain-of-function” type mutant MR (S810L). The organ protective effect was evaluated by histopathological finding in salt-loaded SHR/NDmcr-cp, measuring blood pressure via radiotelemetry, 24-hr urinary albumin excretion, mRNA levels in the kidney, and plasma drug concentrations.

Results

MT-3995 had a highly selective MR antagonistic activity with Ki value of 104 nmol/L (Epl: 84.9 nmol/L). MT-3995 (10,000 nmol/L) had almost no binding affinities for other steroid receptors (GR, PR, AR, ER). Spi and Epl enhanced the transcriptional activity in the mutant MR at therapeutic concentrations. While, MT-3995 (10,000 nmol/L or less) had no effect in the mutant MR. Chronic oral MT-3995 (1, 3, 10 mg/kg, for 4 weeks) prevented the progression of cardiorenal damage with a mild anti-hypertensive effect and suppression of pro-inflammatory and pro-fibrosis mRNA levels in the kidney (osteopontin, MCP-1, TGFb1, Col type1). The renal protective effect at 1mg/kg MT-3995 was equivalent to that of 100mg/kg Epl. The pharmacokinetic data indicated that the renal protective effect of MT-3995 was associated with the long-acting MR blockade around the Ki value all day.

Conclusion

MT-3995 is a highly specific MR antagonist, suggesting no risk of steroid-related adverse effects. MT-3995 has renal protective effect with a long-acting MR blockade around the Ki value, indicating that the avoidance of redundant Cmax elevation would be a strategy to minimize hyperkalemia risk in DN patients.

Funding

  • Commercial Support