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; M. 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. Schaeffer; L. Rhodes; J. E. Drisko; E. McGowan; D. E. MacIntyre; S. Vincent; J. R. Carlin; J. Cameron; R. G. Smith

doi:10.1021/jm000275p

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, M. 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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Abstract

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 language	English
Pages (from-to)	917-922
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	44
Issue number	6
DOIs	https://doi.org/10.1021/jm000275p
State	Published - 15 Mar 2001
Externally published	Yes

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DeVita, R. J., Walsh, T. F., Young, J. R., Jiang, J., Ujjainwalla, F., Toupence, R. B., Parikh, M., Huang, S. X., Fair, J. A., Goulet, M. T., Wyvratt, M. J., Lo, J. L., Ren, N., Yudkovitz, J. B., Yang, Y. T., Cheng, K., Cui, J., Mount, G., Rohrer, S. P., ... Smith, R. G. (2001). A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor. Journal of Medicinal Chemistry, 44(6), 917-922. https://doi.org/10.1021/jm000275p

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

abstract = "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.",

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

year = "2001",

month = mar,

day = "15",

doi = "10.1021/jm000275p",

language = "English",

volume = "44",

pages = "917--922",

journal = "Journal of Medicinal Chemistry",

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DeVita, RJ, Walsh, TF, Young, JR, Jiang, J, Ujjainwalla, F, Toupence, RB, Parikh, M, Huang, SX, Fair, JA, Goulet, MT, Wyvratt, MJ, Lo, JL, Ren, N, Yudkovitz, JB, Yang, YT, Cheng, K, Cui, J, Mount, G, Rohrer, SP, Schaeffer, JM, Rhodes, L, Drisko, JE, McGowan, E, MacIntyre, DE, Vincent, S, Carlin, JR, Cameron, J & Smith, RG 2001, 'A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor', Journal of Medicinal Chemistry, vol. 44, no. 6, pp. 917-922. https://doi.org/10.1021/jm000275p

TY - JOUR

T1 - A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor

AU - DeVita, R. J.

AU - Walsh, T. F.

AU - Young, J. R.

AU - Jiang, J.

AU - Ujjainwalla, F.

AU - Toupence, R. B.

AU - Parikh, M.

AU - Huang, S. X.

AU - Fair, J. A.

AU - Goulet, M. T.

AU - Wyvratt, M. J.

AU - Lo, J. L.

AU - Ren, N.

AU - Yudkovitz, J. B.

AU - Yang, Y. T.

AU - Cheng, K.

AU - Cui, J.

AU - Mount, G.

AU - Rohrer, S. P.

AU - Schaeffer, J. M.

AU - Rhodes, L.

AU - Drisko, J. E.

AU - McGowan, E.

AU - MacIntyre, D. E.

AU - Vincent, S.

AU - Carlin, J. R.

AU - Cameron, J.

AU - Smith, R. G.

PY - 2001/3/15

Y1 - 2001/3/15

N2 - 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.

AB - 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.

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U2 - 10.1021/jm000275p

DO - 10.1021/jm000275p

M3 - Article

C2 - 11300873

AN - SCOPUS:0035866652

SN - 0022-2623

VL - 44

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EP - 922

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 6

ER -

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

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