Toward β‑Secretase‑1 Inhibitors with Improved Isoform Selectivity

BACE1
is responsible for the first step in APP proteolysis, leading
to toxic Aβ production, and has been indicated to play a key
role in the pathogenesis of Alzheimer’s disease. The related
isoform BACE2 is thought to be involved in processing of the pigment
cell-specific melanocyte protein. To avoid potential effects on pigmentation,
we investigated the feasibility for developing isoform-selective BACE1
inhibitors. Cocrystal structures of 47 compounds were analyzed and
clustered according to their selectivity profiles. Selective BACE1
inhibitors were found to exhibit two distinct conformational features
proximal to the flap and the S3 subpocket. Several new molecules were
designed and tested to make use of this observation. The combination
of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in
lead molecule 28, which exhibited ∼50-fold selectivity.
Compared to a nonselective BACE1/2 inhibitor, 28 showed
significantly less inhibition of PMEL processing in human melanocytes,
indicating good functional selectivity of this inhibitor class.