Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs).

Naoya Nagata, Motonori Miyakawa, Seiji Amano, Kazuyuki Furuya, Noriko Yamamoto, Kiyoshi Inoguchi

Central Research Laboratories, Kaken Pharmaceutical Co., Ltd, Yamashina, Kyoto, Japan. nagata_naoya@kaken.co.jp

Bioorganic & medicinal chemistry letters 2011 Mar 15

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Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2 nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo. Copyright © 2011 Elsevier Ltd. All rights reserved.

Citation

Naoya Nagata, Motonori Miyakawa, Seiji Amano, Kazuyuki Furuya, Noriko Yamamoto, Kiyoshi Inoguchi. Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs). Bioorganic & medicinal chemistry letters. 2011 Mar 15;21(6):1744-7