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 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.
authors: 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
authors: R J
authors: RJ
authors: DeVita
authors: T F
authors: TF
authors: Walsh
authors: J R
authors: JR
authors: Young
authors: J
authors: J
authors: Jiang
authors: F
authors: F
authors: Ujjainwalla
authors: R B
authors: RB
authors: Toupence
authors: M
authors: M
authors: Parikh
authors: S X
authors: SX
authors: Huang
authors: J A
authors: JA
authors: Fair
authors: M T
authors: MT
authors: Goulet
authors: M J
authors: MJ
authors: Wyvratt
authors: J L
authors: JL
authors: Lo
authors: N
authors: N
authors: Ren
authors: J B
authors: JB
authors: Yudkovitz
authors: Y T
authors: YT
authors: Yang
authors: K
authors: K
authors: Cheng
authors: J
authors: J
authors: Cui
authors: G
authors: G
authors: Mount
authors: S P
authors: SP
authors: Rohrer
authors: J M
authors: JM
authors: Schaeffer
authors: L
authors: L
authors: Rhodes
authors: J E
authors: JE
authors: Drisko
authors: E
authors: E
authors: McGowan
authors: D E
authors: DE
authors: MacIntyre
authors: S
authors: S
authors: Vincent
authors: J R
authors: JR
authors: Carlin
authors: J
authors: J
authors: Cameron
authors: R G
authors: RG
authors: Smith
mesh_terms: 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
chemical_list: 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