title: Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists.
abstract: Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+/-)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Amdt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: DeVita
authors.forename: M T
authors.initials: MT
authors.lastname: Goulet
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: J L
authors.initials: JL
authors.lastname: Lo
authors.forename: Y T
authors.initials: YT
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D015363:Quinolones; D011966:Receptors, LHRH