RU-59063

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RU-59063
RU-59063.svg
Clinical data
Drug classNonsteroidal androgen; Selective androgen receptor modulator
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC17H18F3N3O2S
Molar mass385.405 g/mol g·mol−1
3D model (JSmol)

RU-59063 is a nonsteroidal androgen or selective androgen receptor modulator (SARM) which was first described in 1994 and was never marketed.[1] It was originally thought to be a potent antiandrogen, but subsequent research found that it actually possesses dose-dependent androgenic activity, albeit with lower efficacy than dihydrotestosterone (DHT).[1][2] The drug is an N-substituted arylthiohydantoin and was derived from the first-generation nonsteroidal antiandrogen (NSAA) nilutamide.[1][3] The second-generation NSAAs enzalutamide, RD-162, and apalutamide were derived from RU-59063.[4][5]

RU-59063 has high affinity for the human androgen receptor (AR) (Ki = 2.2 nM; Ka = 5.4 nM) and 1,000-fold selectivity for the AR over other nuclear steroid hormone receptors, including the PR, ER, GR, and MR.[3][2] It shows 3- and 8-fold higher affinity than testosterone for the rat and human AR, respectively, and up to 100-fold higher affinity for the rat AR than the first-generation NSAAs flutamide, nilutamide, and bicalutamide.[1] It also has slightly higher affinity for the AR than DHT and nearly equal affinity to that of the very-high-affinity AR ligand metribolone (R-1881).[4][6] In addition, RU-59063, unlike testosterone and DHT, shows no specific binding to human plasma.[1]

Affinities of a selection of androgen receptor
ligands at steroid hormone receptors

Compound AR ER PR GR MR
Metribolone 290 < 0.1 190 4 38
Dihydrotestosterone 180 ? ? ? ?
Testosterone 100 ? ? ? ?
Cyproterone acetate 10 ? ? ? ?
Bicalutamide 1.8 ? ? ? ?
Nilutamide 0.8 ? ? ? ?
Hydroxyflutamide 0.8 ? ? ? ?
RU-59063 300 <0.1 <0.1 <0.1 <0.1
RU-58841 150 ? ? ? ?
RU-58642 46 <0.1 <0.1 <0.1 <0.1
RU-57073 163 <0.1 <0.1 <0.1 <0.1
RU-56187 92 <0.1 <0.1 <0.1 <0.1
Notes: Values are RBAs (%). Reference ligands (100%) were testosterone for the AR, estradiol for the ERα and ERβ, progesterone for the PR, dexamethasone for the GR, and aldosterone for the MR. Sources: See template.

See also[edit]

References[edit]

  1. ^ a b c d e Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D (January 1994). "Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor". J. Steroid Biochem. Mol. Biol. 48 (1): 111–9. doi:10.1016/0960-0760(94)90257-7. PMID 8136296.
  2. ^ a b Cadilla R, Turnbull P (2006). "Selective androgen receptor modulators in drug discovery: medicinal chemistry and therapeutic potential". Curr Top Med Chem. 6 (3): 245–70. doi:10.2174/156802606776173456. PMID 16515480.
  3. ^ a b Liu B, Su L, Geng J, Liu J, Zhao G (2010). "Developments in nonsteroidal antiandrogens targeting the androgen receptor". ChemMedChem. 5 (10): 1651–61. doi:10.1002/cmdc.201000259. PMID 20853390.
  4. ^ a b Ran F, Xing H, Liu Y, Zhang D, Li P, Zhao G (2015). "Recent Developments in Androgen Receptor Antagonists". Arch. Pharm. (Weinheim). 348: 757–775. doi:10.1002/ardp.201500187. PMID 26462013.
  5. ^ Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (2009). "Development of a second-generation antiandrogen for treatment of advanced prostate cancer". Science. 324 (5928): 787–90. doi:10.1126/science.1168175. PMC 2981508. PMID 19359544.
  6. ^ Lim AC, Attard G (2013). "Improved therapeutic targeting of the androgen receptor: rational drug design improves survival in castration-resistant prostate cancer". Curr Drug Targets. 14 (4): 408–19. doi:10.2174/1389450111314040003. PMID 23565754.