14063-86-6Relevant articles and documents
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
Yonezawa, Shuji,Fujiwara, Kenichiro,Yamamoto, Takahiko,Hattori, Kazunari,Yamakawa, Hidekuni,Muto, Chie,Hosono, Motoko,Tanaka, Yoshikazu,Nakano, Toru,Takemoto, Hiroshi,Arisawa, Mitsuhiro,Shuto, Satoshi
, p. 6506 - 6522 (2013/10/22)
For further investigation of BACE1 inhibitors using conformational restriction with sp3 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 ～0.5 kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.
