The stability of RAD140 was high (t1/2 > 2 h) in incubations with rat, monkey, and human microsomes, and it also had good bioavailability in rats (F = 27***8722;63%) and monkeys (65***8722;75%). RAD140 demonstrated excellent affinity for the androgen receptor (Ki = 7 nM vs 29 nM for testosterone and 10 nM for DHT) as well as good selectivity over other steroid hormone nuclear receptors, with the closest off target receptor being the progesterone receptor (IC50 = 750 nM vs 0.2 nM for progesterone).18In vitro functional androgen agonist activity was confirmed in the C2C12 osteoblast differentiation assay, where an EC50 of 0.1 nM was shown (DHT = 0.05 nM).
RAD140 demonstrated no stimulation of the prostate above the intact animal control level until the highest dose tested, 30 mg/kg.
In this study, a mean weight gain of greater than 10% in just 28 days of dosing was achieved at a dose of just 0.1 mg/kg, with a similar effect observed at the 1.0 mg/kg dosing group (cynomolgous monkeys).
Clinical chemistry indicated the expected lowering of lipids (LDL, HDL, triglycerides). Despite the rather dramatic increases in body weight over such a short time, there was no elevation of liver enzyme transaminase levels in any animal at any dose >2 fold over its baseline value. Given the well-established relationship between oral androgen use and liver stress indicators, we were quite pleased that at a dose 10-fold greater than the fully effective dose we saw minimal liver enzyme elevations.
Taken in sum, RAD140 has all the hallmarks of a SARM. It is potency selective, since it stimulates muscle weight increases at a lower dose than that required to stimulate prostate weight increases. Moreover, it is also efficacy selective, because it is fully anabolic on muscle but demonstrates less than complete efficacy on the prostate and seminal vesicles and, in fact, can partially antagonize the stimulation of the seminal vesicles induced by testosterone. RAD140 has excellent pharmacokinetics and is a potent anabolic in nonhuman primates as well. We believe the overall preclinical profile of RAD140 is very good, and the compound has completed preclinical toxicology in both rats and monkeys. We are currently preparing RAD140 for phase I clinical studies in patients suffering from severe weight loss due to cancer cachexia.
