A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.
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 10(4)-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.
DeVita
R J
RJ
Departments of Medicinal Chemistry, Biochemistry & Physiology, Pharmacology, and Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. robert_devita@merck.com
Walsh
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JR
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Ujjainwalla
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Toupence
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RB
Parikh
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Huang
S X
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Fair
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JA
Goulet
M T
MT
Wyvratt
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MJ
Lo
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JL
Ren
N
N
Yudkovitz
J B
JB
Yang
Y T
YT
Cheng
K
K
Cui
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J
Mount
G
G
Rohrer
S P
SP
Schaeffer
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JM
Rhodes
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L
Drisko
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McGowan
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MacIntyre
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D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D010902:Pituitary Gland / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C424434:4-(2-(azetidin-2-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide; D001384:Azetidines; D015363:Quinolones; D011966:Receptors, LHRH