title: Conformational restriction approach to BACE1 inhibitors II: SAR study of the isocytosine derivatives fixed with a cis-cyclopropane ring.
abstract: To improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring.
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd, Kita-21 Nishi-11 Kita-ku, Sapporo 001-0021, Japan. shuji.yonezawa@shionogi.co.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Yonezawa
authors.forename: Hidekuni
authors.initials: H
authors.lastname: Yamakawa
authors.forename: Chie
authors.initials: C
authors.lastname: Muto
authors.forename: Motoko
authors.initials: M
authors.lastname: Hosono
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hattori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togame
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemoto
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; C093270:isocytosine; D003596:Cytosine; C030797:cyclopropane; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human