8 research outputs found
Acyl Guanidine Inhibitors of β‑Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
No full textThis report describes the discovery and optimization
of a BACE-1
inhibitor series containing an unusual acyl guanidine chemotype that
was originally synthesized as part of a 6041-membered solid-phase
library. The synthesis of multiple follow-up solid- and solution-phase
libraries facilitated the optimization of the original micromolar
hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand
binding and cell-based functional assay formats. The X-ray structure
of representative inhibitors bound to BACE-1 revealed a number of
key ligand:protein interactions, including a hydrogen bond between
the side chain amide of flap residue Gln73 and the acyl guanidine
carbonyl group, and a cation−π interaction between Arg235
and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous
administration in rats, an acyl guanidine inhibitor with single-digit
nanomolar activity in cells afforded good plasma exposures and a dose-dependent
reduction in plasma Aβ levels, but poor brain exposure was observed
(likely due to Pgp-mediated efflux), and significant reductions in
brain Aβ levels were not obtained
