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ChemMedChem. 2014 Jan;9(1):197-206. doi: 10.1002/cmdc.201300348. Epub 2013 Nov 22.

Lead evaluation of tetrahydroquinolines as nonsteroidal selective androgen receptor modulators for the treatment of osteoporosis.

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Central Research Laboratories, Kaken Pharmaceutical Co. Ltd. 14 Shinomiya, Minamikawara-cho, Yamashina, Kyoto 607-8042 (Japan).


Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano-group-containing THQ (CN-THQ) to the agonist function and optimized CN-THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para-substituted aromatic ring attached through an amide linker. The long-tail THQ derivative 6-acetamido-N-(2-(8-cyano-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl)-2-methylpropyl)nicotinamide (1 d), which bears a para-acetamide-substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.


androgen receptors; docking; osteoanabolic activity; selective androgen receptor modulators; tetrahydroquinolines

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