title: Conformational restriction approach to β-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode.
abstract: Improvement of a drug's binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors.
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Kita-21 Nishi-11 Kita-ku, Sapporo 001-0021, Japan. shu@pharm.hokudai.ac.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Yonezawa
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamamoto
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: Kazunari
authors.initials: K
authors.lastname: Hattori
authors.forename: Kenichi
authors.initials: K
authors.lastname: Higashino
authors.forename: Takashi
authors.initials: T
authors.lastname: Yutsudo
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
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*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D019277:Entropy; D004797:Enzyme-Linked Immunosorbent Assay; D005453:Fluorescence; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D011743:Pyrimidines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human