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.
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.
Tucci
Fabio C
FC
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
Zhu
Yun-Fei
YF
Struthers
R Scott
RS
Guo
Zhiqiang
Z
Gross
Timothy D
TD
Rowbottom
Martin W
MW
Acevedo
Oscar
O
Gao
Yinghong
Y
Saunders
John
J
Xie
Qiu
Q
Reinhart
Greg J
GJ
Liu
Xin-Jun
XJ
Ling
Nicholas
N
Bonneville
Anne K L
AK
Chen
Takung
T
Bozigian
Haig
H
Chen
Chen
C
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
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