Identification of a 4-(Hydroxymethyl)diarylhydantoin as a Selective Androgen Receptor Modulator

被引：48

作者：

Nique, Francois ^{[1
]}

Hebbe, Severine ^{[1
]}

Triballeau, Nicolas ^{[1
]}

Peixoto, Christophe ^{[1
]}

Lefrancois, Jean-Michel ^{[1
]}

Jary, Helene ^{[1
]}

Alvey, Luke ^{[1
]}

Manioc, Murielle ^{[1
]}

Housseman, Christopher ^{[1
]}

Klaassen, Hugo ^{[1
]}

Van Beeck, Kris ^{[1
]}

Guedin, Denis ^{[1
]}

Namour, Florence ^{[1
]}

Minet, Dominque ^{[1
]}

Van der Aar, Ellen ^{[1
]}

Feyen, Jean ^{[1
]}

Fletcher, Stephen ^{[1
]}

Blanque, Roland ^{[1
]}

Robin-Jagerschmidt, Catherine ^{[1
]}

Deprez, Pierre ^{[1
]}

机构：

[1] GALAPAGOS, F-93230 Romainville, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 19期

关键词：

TESTOSTERONE; DERIVATIVES; DISCOVERY; THERAPY; LIGANDS; RISKS;

D O I：

10.1021/jm300281x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structural modification performed on a 4-methyl-4-(4-hydroxyphenyphyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.

引用

页码：8236 / 8247

页数：12

共 30 条

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