title: Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity.
abstract: Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. cchen@neurocrine.com
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Joseph
authors.initials: J
authors.lastname: Pontillo
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Huang
authors.forename: Dongpei
authors.initials: D
authors.lastname: Wu
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Martin
authors.initials: M
authors.lastname: Rowbottom
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Warren
authors.initials: W
authors.lastname: Wade
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000882:Haplorhini; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D014498:Uracil; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human