A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor

R. J. DeVita, T. F. Walsh, J. R. Young, J. Jiang, F. Ujjainwalla, R. B. Toupence, Mamta Parikh, S. X. Huang, J. A. Fair, M. T. Goulet, M. J. Wyvratt, J. L. Lo, N. Ren, J. B. Yudkovitz, Y. T. Yang, K. Cheng, J. Cui, G. Mount, S. P. Rohrer, J. M. SchaefferL. Rhodes, J. E. Drisko, E. McGowan, D. E. MacIntyre, S. Vincent, J. R. Carlin, J. Cameron, R. G. Smith

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54 Scopus citations


Extensive development of the structure - activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl) -1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 104-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.

Original languageEnglish (US)
Pages (from-to)917-922
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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