Design, synthesis, and preclinical characterization of the selective androgen receptor modulator (SARM) RAD140

ACS Medicinal Chemistry Letters

Volumn 2, Issue 2, 2011, Pages 124-129

  Miller, Chris P ^a   Shomali, Maysoun ^a   Lyttle, C Richard ^a   O'dea, Louis St L ^a   Herendeen, Hillary ^a   Gallacher, Kyla ^a   Paquin, Dottie ^a   Compton, Dennis R ^b   Sahoo, Bishwabhusan ^b   Kerrigan, Sean A ^b   Burge, Matthew S ^b   Nickels, Michael ^b   Green, Jennifer L ^b   Katzenellenbogen, John A ^c   Tchesnokov, Alexei ^d   Hattersley, Gary ^a  

^a Radius Health Inc   (United States)

^b Obiter Research   (United States)

^c UNIVERSITY OF ILLINOIS AT URBANA CHAMPAIGN   (United States)

^d Cambridge Major Laboratories Inc   (United States)

Author keywords

Androgen; cachexia; Herschberger assay; oxadiazole; primate; SARM

Indexed keywords

ANDROSTANOLONE; ANTIANDROGEN; BMS 562929; GTX S 22; RAD 140; SELECTIVE ANDROGEN RECEPTOR MODULATOR; TESTOSTERONE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG DOSE INCREASE; DRUG MECHANISM; DRUG MEGADOSE; DRUG SYNTHESIS; MALE; NONHUMAN; PRIORITY JOURNAL; RAT;

PRIMATES;

EID: 79951521699     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml1002508     Document Type: Article

References (32)

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10. p K data in rats for compound 3 is provided in the Supporting Information.
11. Oral data for compounds 3 and 4 in the Herschberger assay is shown in the Supporting Information.
12. Human and rat microsome data are shown in the Supporting Information.
13. The left-hand side of the molecule as written is presumed to overlay with the A-ring of testosterone. This particular left-hand side equivalent has been utilized to good effect previously in nonsteroidal SARMs: Li, J. J.; Sutton, J. C.; Nirschl, A.; Zou, Y.; Wang, H.; Sun, C.; Pi, Z.; Johnson, R.; Krystek, S. R., Jr.; Seethala, R.; Golla, R.; Sleph, P. G.; Beehler, B. C.; Grover, G. J.; Fura, A.; Vyas, V. P.; Li, C. Y.; Gougoutas, J. Z.; Galella, M. A.; Michael, A.; Zahler, R.; Ostrowski, J.; Hamann, L. G. Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications J. Med. Chem. 2007, 50 (13) 3015-3025. The precursor fragment 6 has been described for the preparation of SARMs in (Pubitemid 47001244)
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18. The scheme shown was used to successfully produce approximately 2 kg of compound 5 in >99% purity under GMP manufacturing conditions.
19. d = 25 nM (fluorometric R1881), and [S] = 1.
20. The C2C12 osteoblast differentiation assay procedure is explained in the Supporting Information.
21. Hershberger, L. G.; Shipley, E. G.; Meyer, R. K. Myotropic activity of 19-nortestosterone and other steroids determined by a modified levator ani muscle method Proc. Soc. Exp. Biol. Med. 1953, 83, 175-80
22. 90 on muscle in our Herschberger assays.
23. RAD140 demonstrated fairly linear increases in exposure in male rats up through the 10 mg/kg po dose range, thereby ruling out an exposure limited efficacy as opposed to compound-limited efficacy. Antagonism of TP is further evidence of a mechanism-specific, limited efficacy as opposed to a pharmacokinetic limitation of the compound.
24. Testosterone levels in castrated rats are <0.5 ng/mL; i.e. see: DSouza, S. S.; Selmin, F.; Murty, S. B.; Qiu, W.; Thanoo, B. C.; DeLuca, P. P. Assessment of fertility in male rats after extended chemical castration with a GNRH antagonist AAPS. Pharm. Sci. 2004, 6 (1), Article 10.
25. 70 for testosterone was in this model.
26. The monkeys were placed into groups of three at day-21, and the weight of each monkey recorded at each time point and the mean weight of each group are reflected on the graph. Coincidentally, by day -1, the mean weight of each group had each converged to a very similar value of 4.26 kg, 4.29 kg, and 4.28 kg for the 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg groups, respectively.
27. p K analysis at various time points throughout this monkey study indicated that significant increases in exposure were seen with dose.
28. Since these were young, intact male cynomolgous monkeys (3 to 4 years of age), they had fairly high endogeneous total plasma testosterone at day -1 (approximately 600-800 ng/dL), which is similar to the approximately 600 ng/mL that human males have between the ages of 25 and 54 (the levels then gradually decline with age). After 28 days of dosing with RAD140, the testosterone levels in all three groups was suppressed to approximately 200-300 ng/dL, with similar suppression in all three groups, although testosterone levels were significantly different for only the 0.01 mg/kg group (p < 0.05). Although this measurement did not account for possible diurnal variations in the animals and LH levels were not definitive, since they were below the level of detection in most pre- and postdose groups (LH < 0.8 ng/mL), one might still consider the possibility that even the 0.01 mg/kg dose was a fully effective, testosterone replacement dose, since body weight and lean mass were at least maintained (if not increased) in the low dose group despite significant testosterone suppression. Beyond this finding, we do not know whether testosterone suppression is a proxy for other CNS-related androgen effects beyond LH interference, such as mood, libido, and cognition, but we do believe a SARM with potent androgen agonist, CNS-type activity would be an interesting tool for that sort of exploration.
29. For a thorough examination of the effect of high dose, injected dihydrotestosterone (DHT) on lipids in female, ovariectomized cynomolgus monkeys, see: Nantermet, P.; Harada, S.; Liu, Y.; Spring, C.; Johnson, C.; Yu, Y.; Kimme, D.; Holder, D.; Phillips, R.; Ray, W. Gene expression analysis in cynomolgus monkeys provides mechanistic insight into high-density liproprotein-cholesterol reduction by androgens in primates Endocrinology 2008, 149 (4) 1551-1561 (Pubitemid 351468320)
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31. Mean triglyceride changes by group were (-26%, -36%, -37%), LDL (+8%, -24%, -53%), and HDL (-13%, -42%, -64%) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively. Mean liver enzyme (ALT) changes by group were (ALT) (-15%, -2%, +43%) and (ALP) (-9%, +3%, +31%) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively.
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