Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers

Abstract

Apararenone is a long‐acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single‐ and multiple‐dose apararenone were assessed in 3 phase 1 randomized, double‐blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single‐dose apararenone (3.75–640 mg) and multiple‐dose apararenone (10–40 mg/day on days 1–14, 320 mg loading dose on day 1 + 10 mg/day on days 2–14, or 40–320 mg loading dose on day 1 + 2.5–20 mg/day on days 2–14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single‐dose apararenone (5–320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single‐dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose‐proportional increase was observed in PK parameters over the apararenone dose range of 3.75–40 mg; at higher doses, a less than dose‐proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half‐life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.

Novel non‐steroidal mineralocorticoid receptor antagonists in cardiorenal disease

“…Apararenone exerts a high selectivity for the MR, with IC 50 values for the androgen, progesterone and glucocorticoid receptors above 100 μM (Nakamura & Kawaguchi, 2021). The molecular binding mode to the MR has not been reported.…”

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…) is a benzoxazinone derivative [104]. It is a long-acting, highly selective MRA [105,106]. Its major metabolite is 1118174, which has 1/50 of apararenone's affinity to bind to the MR.…”

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

“…Therefore, in order to overcome these issues, the development of selective and potent MRAs is required, and extensive research has been conducted to identify novel nonsteroidal MRAs. , Compared with steroidal MRAs, nonsteroidal MRAs characterized by high MR selectivity are suggested to reduce the risk of hyperkalemia. − As a result of the compound optimization, some compounds have reached the stage of clinical development. − Notably, the most advanced compounds in this context are esaxerenone (CS-3150), which received marketing approval in Japan for the treatment of hypertension in 2019, finerenone (BAY94-8862), which was approved in the United States for the treatment of chronic kidney disease associated with type 2 diabetes in 2021, apararenone (MT-3995), KBP-5074, and AZD9977 (Figure ). In this article, we describe the design and discovery of 19 (apararenone: MT-3995), as well as the pharmacological profile of the said compound, which has completed phase II clinical trials for diabetic nephropathy and NASH, wherein it proved to be a highly selective and potent nonsteroidal MRA. − …”