A selective androgen receptor modulator SARM-2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys

Abstract

SARM-2f a selective androgen receptor (AR) modulator, increases skeletal muscle mass and locomotor activity in rats. This study aimed to clarify its pharmacological effects in monkeys. In reporter assays, the EC₅₀ values of SARM-2f for rat, monkey, and human AR were 2.5, 3, and 3.6 nmol/L, respectively; those of testosterone were 12, 3.2, and 11 nmol/L, respectively. A single oral administration (10 mg/kg SARM-2f) produced a maximal plasma concentration of 3011 ng/mL, with an area under the 24 hours concentration-time curve of 8152 ng·h/mL in monkeys. Body weight (BW), lean body mass (LBM), and plasma levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein (a), alanine aminotransferase, and asparagine aminotransferase were measured after 4 weeks of treatment with SARM-2f (1, 3, and 10 mg/kg/day, QD, p.o.) or testosterone enanthate (TE; 2 mg/kg/2 weeks, s.c.) in monkeys. BW and LBM were significantly increased by 12% each by SARM-2f at 10 mg/kg, and by 5% and 8%, respectively, by TE, but these effects were not statistically significant. Plasma levels of all lipids were either decreased or showed a tendency to be decreased by SARM-2f. TE decreased the triglyceride level and increased the low-density lipoprotein cholesterol level. Liver marker levels were not changed by either SARM-2f or TE. Our data demonstrated that SARM-2f exerted anabolic effects and produced a lipid profile that differed from that produced by testosterone in monkeys, suggesting that SARM-2f might be useful for diseases such as sarcopenia.

Keywords: body weight; cholesterol; lean body mass; monkey; sarcopenia; selective androgen receptor modulator; testosterone.

Figure 1

Androgen receptor (AR) transcriptional activity of SARM‐2f, ostarine and testosterone. The reporter assays using COS7 cells expressing (A) monkey AR; (B) human AR; and (C) rat AR were conducted as described in the Methods section. The AR agonistic activities are expressed relative to those of the 1 μmol/L dihydrotestosterone (DHT) treatment as 100%. Luciferase activities for 1 μmol/L DHT in monkey, human and rat ARs were 119 453 ± 19 175 cps, 104 280 ± 9931 cps, and 100 160 ± 8.508 cps, respectively. Data are shown as the mean ± SD (n = 3)

Figure 2

Anabolic effects of SARM‐2f and testosterone enanthate (TE) in monkeys. Male cynomolgus monkeys were treated with daily oral SARM‐2 (1, 3, or 10 mg/kg) or intramuscular injections once every 2 wks of TE (2 mg/kg) for 4 wks. Individual data of (A) body weight (BW) on Days 6, 13, 20, and 27 and (B) lean body mass (LBM) on Days 13 and 28 are shown in the figure. The average value is shown as horizontal lines in each group (n = 3). BW increased significantly on Day 27 by 10 mg/kg SARM‐2f. LBM also showed a significant increase on Day 28 by 10 mg/kg SARM‐2f. TE, as well as 1 and 3 mg/kg SARM‐2f, showed no significant increase of BW and LBM during the study period. *P < .05 by Student's t test, with Bonferroni correction for repeated measurements

Figure 3

Plasma lipid levels after 4‐wk treatments with SARM‐2f or testosterone enanthate (TE) in monkeys. Male cynomolgus monkeys were treated with daily oral SARM‐2 (1, 3, or 10 mg/kg) or intramuscular injections once every 2 weeks of TE (2 mg/kg) for 4 wks. Plasma levels of (A) triglyceride (TG); (B) total cholesterol(T‐chol); (C) low‐density lipoprotein cholesterol (LDL‐c); (D) high‐density lipoprotein cholesterol (HDL‐c); (E) HDL‐c/LDL‐c ratio; and (F) lipoprotein (a)(Lp(a)) are shown. SARM‐2f significantly reduced the TG, T‐chol, and LDL‐c levels at all doses and reduced the HDL‐c level significantly at 3 and 10 mg/kg. TE significantly reduced the TG level and increased the LDL‐c level. Data represent the mean ± SD(n = 3); The effects of SARM‐2f on lipid levels were analyzed by Dunnett's test, and those of testosterone were analyzed by Student's t test. *P < .05, **P < .01 by Dunnett's. ^# P < .05 by Student's t test

Figure 4

Liver function tests after 4‐wk treatments with SARM‐2f or testosterone enanthate (TE) in monkeys. Male cynomolgus monkeys were treated with daily oral SARM‐2 (1, 3, or 10 mg/kg) or intramuscular injections once every 2 wks of TE (2 mg/kg) for 4 wks. Plasma levels of (A) asparagine aminotransferase (AST); (B) alanine aminotransferase (ALT) are shown. Treatment with SARM‐2f or TE did not alter the ALT and AST levels, either. Data represent the mean ± SD(n = 3); The effects of SARM‐2f on ALT and AST levels were analyzed by Dunnett's test, and those of testosterone were analyzed by Student's t test