title: Identification of a 4-(hydroxymethyl)diarylhydantoin as a selective androgen receptor modulator.
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.
authors.affiliation: GALAPAGOS, Parc Biocitech, 102 Avenue Gaston Roussel, 93230 Romainville, France.
authors.forename: François
authors.initials: F
authors.lastname: Nique
authors.forename: Séverine
authors.initials: S
authors.lastname: Hebbe
authors.forename: Nicolas
authors.initials: N
authors.lastname: Triballeau
authors.forename: Christophe
authors.initials: C
authors.lastname: Peixoto
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Lefrançois
authors.forename: Hélène
authors.initials: H
authors.lastname: Jary
authors.forename: Luke
authors.initials: L
authors.lastname: Alvey
authors.forename: Murielle
authors.initials: M
authors.lastname: Manioc
authors.forename: Christopher
authors.initials: C
authors.lastname: Housseman
authors.forename: Hugo
authors.initials: H
authors.lastname: Klaassen
authors.forename: Kris
authors.initials: K
authors.lastname: Van Beeck
authors.forename: Denis
authors.initials: D
authors.lastname: Guédin
authors.forename: Florence
authors.initials: F
authors.lastname: Namour
authors.forename: Dominque
authors.initials: D
authors.lastname: Minet
authors.forename: Ellen
authors.initials: E
authors.lastname: Van der Aar
authors.forename: Jean
authors.initials: J
authors.lastname: Feyen
authors.forename: Stephen
authors.initials: S
authors.lastname: Fletcher
authors.forename: Roland
authors.initials: R
authors.lastname: Blanqué
authors.forename: Catherine
authors.initials: C
authors.lastname: Robin-Jagerschmidt
authors.forename: Pierre
authors.initials: P
authors.lastname: Deprez
mesh_terms: D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D054333:Drug Partial Agonism; D006367:HeLa Cells; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C577110:4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; D045930:Anabolic Agents; D059002:Androgen Receptor Antagonists; D000728:Androgens; D006827:Hydantoins; D011944:Receptors, Androgen