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

被引：16

作者：

Nagata, Naoya ^{[1
]}

Miyakawa, Motonori ^{[1
]}

Amano, Seiji ^{[1
]}

Furuya, Kazuyuki ^{[1
]}

Yamamoto, Noriko ^{[1
]}

Inoguchi, Kiyoshi ^{[1
]}

机构：

[1] Kaken Pharmaceut Co Ltd, Cent Res Labs, Yamashina Ku, Kyoto 6078042, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 06期

关键词：

SARM; Nonsteroidal AR agonist; THQ; Four-point pharmacophore requirement; Grieco; 3CC; 3 COMPONENT CONDENSATION; SOLID SUPPORT SYNTHESIS; TESTOSTERONE; ALDEHYDES; PROSTATE; THERAPY; POTENT; RISKS; MEN;

D O I：

10.1016/j.bmcl.2011.01.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (EC50 = 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. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：1744 / 1747

页数：4

共 27 条

[1]

[Anonymous], 2009, MAESTR VERS 9 0

[2]

[Anonymous], 2009, JAG VERS 7 6

[3]

[Anonymous], QIKPROP VERS 3 2

[4] Risks versus benefits of testosterone therapy in elderly men [J].

Basaria, S ;

Dobs, AS .

DRUGS & AGING, 1999, 15 (02) :131-142

[5]

BRUEGGEMIER RW, 1995, PRINCIPLES MED CHEM, P486

[6] ANTIANDROGENIC STEROIDAL SULFONYLPYRAZOLES [J].

CHRISTIANSEN, RG ;

BELL, MR ;

DAMBRA, TE ;

MALLAMO, JP ;

HERRMANN, JL ;

ACKERMAN, JH ;

OPALKA, CJ ;

KULLNIG, RK ;

WINNEKER, RC ;

SNYDER, BW ;

BATZOLD, FH ;

SCHANE, HP .

JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (08) :2094-2100

[7] The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor [J].

Estébanez-Perpiña, E ;

Moore, JMR ;

Mar, E ;

Delgado-Rodrigues, E ;

Nguyen, P ;

Baxter, JD ;

Buehrer, BM ;

Webb, P ;

Fletterick, RJ ;

Guy, RK .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (09) :8060-8068

[8] THE STEROID AND THYROID-HORMONE RECEPTOR SUPERFAMILY [J].

EVANS, RM .

SCIENCE, 1988, 240 (4854) :889-895

[9] Acidic heterocycles as novel hydrophilic pharmacophore of androgen receptor ligands with a carborane core structure [J].

Fujii, Shinya ;

Ohta, Kiminori ;

Goto, Tokuhito ;

Kagechika, Hiroyuki ;

Endo, Yasuyuki .

BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (01) :344-350

[10] Chemistry and structural biology of androgen receptor [J].

Gao, WQ ;

Bohl, CE ;

Dalton, JT .

CHEMICAL REVIEWS, 2005, 105 (09) :3352-3370

← 1 2 3 →