Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity

Chen Chen; Yongsheng Chen; Joseph Pontillo; Zhiqiang Guo; Charles Q Huang; Dongpei Wu; Ajay Madan; Takung Chen; Jenny Wen; Qiu Xie; Fabio C Tucci; Martin Rowbottom; Yun-Fei Zhu; Warren Wade; John Saunders; Haig Bozigian; R Scott Struthers

doi:10.1016/j.bmcl.2008.04.036

Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity

Bioorg Med Chem Lett. 2008 Jun 1;18(11):3301-5. doi: 10.1016/j.bmcl.2008.04.036. Epub 2008 Apr 26.

Authors

Chen Chen¹, Yongsheng Chen, Joseph Pontillo, Zhiqiang Guo, Charles Q Huang, Dongpei Wu, Ajay Madan, Takung Chen, Jenny Wen, Qiu Xie, Fabio C Tucci, Martin Rowbottom, Yun-Fei Zhu, Warren Wade, John Saunders, Haig Bozigian, R Scott Struthers

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. [email protected]

PMID: 18442910
DOI: 10.1016/j.bmcl.2008.04.036

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.

MeSH terms

Animals
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors*
Gonadotropin-Releasing Hormone / antagonists & inhibitors*
Haplorhini
Humans
Inhibitory Concentration 50
Molecular Structure
Rats
Receptors, LHRH / antagonists & inhibitors*
Structure-Activity Relationship
Uracil / analogs & derivatives*
Uracil / chemical synthesis*
Uracil / pharmacokinetics

Substances

Cytochrome P-450 CYP3A Inhibitors
Receptors, LHRH
Gonadotropin-Releasing Hormone
Uracil
Cytochrome P-450 CYP3A
CYP3A4 protein, human