title: Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.
abstract: AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.
authors.affiliation: Paradigm Therapeutics Ltd. (now Takeda Cambridge Ltd.), 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Barnes
authors.forename: Christian
authors.initials: C
authors.lastname: Burschka
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Büttner
authors.forename: Richard
authors.initials: R
authors.lastname: Conroy
authors.forename: Jürgen O
authors.initials: JO
authors.lastname: Daiss
authors.forename: Ian C
authors.initials: IC
authors.lastname: Gray
authors.forename: Alan G
authors.initials: AG
authors.lastname: Hendrick
authors.forename: L H
authors.initials: LH
authors.lastname: Tam
authors.forename: Diana
authors.initials: D
authors.lastname: Kuehn
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
authors.forename: John S
authors.initials: JS
authors.lastname: Mills
authors.forename: Philip
authors.initials: P
authors.lastname: Mitchell
authors.forename: John G
authors.initials: JG
authors.lastname: Montana
authors.forename: Parameswary A
authors.initials: PA
authors.lastname: Muniandy
authors.forename: Helen
authors.initials: H
authors.lastname: Rapley
authors.forename: Graham A
authors.initials: GA
authors.lastname: Showell
authors.forename: David
authors.initials: D
authors.lastname: Tebbe
authors.forename: Reinhold
authors.initials: R
authors.lastname: Tacke
authors.forename: Julie B H
authors.initials: JB
authors.lastname: Warneck
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006727:Hormone Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009919:Orchiectomy; D017208:Rats, Wistar; D011966:Receptors, LHRH / Q000235:genetics; D012825:Silicon / Q000737:chemistry; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C464763:AG045572; D005663:Furans; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D013764:Tetrahydronaphthalenes; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D012825:Silicon