Discovery of Apararenone (MT-3995) as a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

DOI
  • Iijima Toru
    Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation Lead Exploration Unit, Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo
  • Akatsuka Hidenori
    Human Resources Department, Mitsubishi Tanabe Pharma Corporation Quality Assurance Dept., SUN CHEMICAL CO., LTD.
  • Takedomi Kei
    Modality Laboratories, Sohyaku. Innovative Reseach Division, Mitsubishi Tanabe Pharma Corporation Pharma IS/IT Department, Information Systems & Technology Division, Mitsubishi Tanabe Pharma Corporation

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Other Title
  • 新規非ステロイド型ミネラロコルチコイド受容体拮抗薬apararenone（MT-3995）の創製

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Abstract

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, heart failure, and kidney disease. Thus, MR antagonists are expected to be beneficial to patients with these diseases. Steroidal MR antagonists are already marketed and exhibit clinical efficacy. However, they suffer from substantial drawbacks that limit their clinical use. To overcome these issues, we searched for selective and potent nonsteroidal MR antagonists. Based on the structural features of intrinsic ligands and the mechanism of steroid hormone receptor activation, we hypothesized that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a protruding bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. As a result of the search guided by the hypothesis, we discovered apararenone (MT-3995), as a highly selective, potent, and novel nonsteroidal MR antagonist.

Journal

  • MEDCHEM NEWS

    MEDCHEM NEWS 32 (3), 154-159, 2022-08-01

    The Pharmaceutical Society of Japan

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