title: Replacement of the quinoline system in 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonists.
abstract: Results from a medicinal chemistry approach aimed at replacing the quinoline ring system in the potent and selective human neurokinin-3 (hNK-3) receptor antagonists 1-4 of general formula I are discussed. The data give further insight upon the potential NK-3 pharmacophore. In particular, it is highlighted that both the benzene-condensed ring and the quinoline nitrogen are crucial determinants for optimal binding affinity to the hNK-3 receptor. Some novel compounds maintained part of the binding affinity to the receptor (5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, appears to be suitable for further modifications; it offers the option to introduce electron-withdrawing groups at position 2 and 4, conferring on the ring an overall electron-deficiency similar to that of the quinoline.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham S.p.A., Milan, Italy. giuseppe_giardina@sbphrd.com
authors.forename: G A
authors.initials: GA
authors.lastname: Giardina
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: S
authors.initials: S
authors.lastname: Cavagnera
authors.forename: A
authors.initials: A
authors.lastname: Cerri
authors.forename: E
authors.initials: E
authors.lastname: Consolandi
authors.forename: S
authors.initials: S
authors.lastname: Gagliardi
authors.forename: D
authors.initials: D
authors.lastname: Graziani
authors.forename: M
authors.initials: M
authors.lastname: Grugni
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: M A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: R
authors.initials: R
authors.lastname: Mena
authors.forename: L F
authors.initials: LF
authors.lastname: Raveglia
authors.forename: R
authors.initials: R
authors.lastname: Rigolio
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
authors.forename: D B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: G
authors.initials: G
authors.lastname: Zanoni
authors.forename: C
authors.initials: C
authors.lastname: Farina
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; D018042:Receptors, Neurokinin-3