Identification of a 4-(hydroxymethyl)diarylhydantoin as a selective androgen receptor modulator

  • J Med Chem. 2012 Oct 11;55(19):8236-47. doi: 10.1021/jm300281x.
François Nique  1 ,  Séverine Hebbe ,  Nicolas Triballeau ,  Christophe Peixoto ,  Jean-Michel Lefrançois ,  Hélène Jary ,  Luke Alvey ,  Murielle Manioc ,  Christopher Housseman ,  Hugo Klaassen ,  Kris Van Beeck ,  Denis Guédin ,  Florence Namour ,  Dominque Minet ,  Ellen Van der Aar ,  Jean Feyen ,  Stephen Fletcher ,  Roland Blanqué ,  Catherine Robin-Jagerschmidt ,  Pierre Deprez
Affiliations
  • 1. GALAPAGOS, Parc Biocitech, 102 Avenue Gaston Roussel, 93230 Romainville, France.
PMID: 22957947 DOI: 10.1021/jm300281x
Abstract

Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)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.

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