Conformational restriction approach to β-secretase (BACE1) inhibitors III: effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations.
For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.
Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd, Kita-21 Nishi-11 Kita-ku, Sapporo 001-0021, Japan; Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: shuji.yonezawa@shionogi.co.jp.
Shuji
S
Yonezawa
Kenichiro
K
Fujiwara
Takahiko
T
Yamamoto
Kazunari
K
Hattori
Hidekuni
H
Yamakawa
Chie
C
Muto
Motoko
M
Hosono
Yoshikazu
Y
Tanaka
Toru
T
Nakano
Hiroshi
H
Takemoto
Mitsuhiro
M
Arisawa
Satoshi
S
Shuto
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000577:Amides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s disease; Conformational restriction; Cyclopropane; Isothermal titration calorimetry; β-Secretase (BACE1)