title: Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.
abstract: As a part of our continuing research on NPY-Y5 receptor antagonists in the series of novel 6-methoxybenzo[a]cycloheptene derivatives, we discovered a novel skeleton, 7-methoxy-1-hydroxytetraline 7 which had been used as an intermediate, to be more suitable for increasing potencies leading to compound 3 (FR230481). Additionally, we discovered that the naphthalenesulfonamide moiety which was thought to be an essential pharmacophore could be replaced by the 5-chlorobenzothiazolin-3-acetic acid moiety to lead to potent compound 4 (FR233118). The structure-activity relationships on compounds 3,4 and their related derivatives are described. Unfortunately, although compounds 3 and 4 had very high affinities for Y5 receptors, their poor permeabilities to brain were shown by exo-vivo binding assays when orally administered.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, 532-8514, Osaka, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Itani
authors.forename: Harunobu
authors.initials: H
authors.lastname: Ito
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hatakeyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oohashi
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Satoh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D017476:Receptors, Neuropeptide Y; D013764:Tetrahydronaphthalenes; C100568:neuropeptide Y5 receptor