title: 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization.
abstract: Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Martin W
authors.initials: MW
authors.lastname: Rowbottom
authors.forename: Oscar
authors.initials: O
authors.lastname: Acevedo
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Gao
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: Xin-Jun
authors.initials: XJ
authors.lastname: Liu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ling
authors.forename: Anne K L
authors.initials: AK
authors.lastname: Bonneville
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009919:Orchiectomy; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C498569:3-(2-amino-2-phenylethyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione; D011966:Receptors, LHRH; D013941:Thymine