1 research outputs found
Conformational Restriction Approach to β‑Secretase (BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode
Improvement of a drug’s binding activity using
the conformational
restriction approach with sp<sup>3</sup> 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 <b>2</b> was replaced with chiral cyclopropane rings. The synthesis
and biologic evaluation of these compounds revealed that the <i>cis</i>-(1<i>S</i>,2<i>R</i>) isomer <b>6</b> exhibited the most potent BACE1 inhibitory activity among
them. X-ray structure analysis of the complex of <b>6</b> 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 <b>6</b> 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