title: Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists.
abstract: Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC(50)=0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC(50) of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3 inverse agonists.
authors.affiliation: Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Jitsuoka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsukahara
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenaga
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato