Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity.
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.
Chen
Chen
C
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. cchen@neurocrine.com
Chen
Yongsheng
Y
Pontillo
Joseph
J
Guo
Zhiqiang
Z
Huang
Charles Q
CQ
Wu
Dongpei
D
Madan
Ajay
A
Chen
Takung
T
Wen
Jenny
J
Xie
Qiu
Q
Tucci
Fabio C
FC
Rowbottom
Martin
M
Zhu
Yun-Fei
YF
Wade
Warren
W
Saunders
John
J
Bozigian
Haig
H
Struthers
R Scott
RS
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
D065692:Cytochrome P-450 CYP3A Inhibitors; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D014498:Uracil; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human