Creation of Novel Cores for β‑Secretase
(BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy
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Abstract
In order to find optimal core structures
as starting points for
lead optimization, a multiparameter lead generation workflow was designed
with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer’s
disease. De novo design of core fragments was connected with three
predictive in silico models addressing target affinity, permeability,
and hERG activity, in order to guide synthesis. Taking advantage of
an additive SAR, the prioritized cores were decorated with a few,
well-characterized substituents from known BACE-1 inhibitors in order
to allow for core-to-core comparisons. Prediction methods and analyses
of how physicochemical properties of the core structures correlate
to in vitro data are described. The syntheses and in vitro data of
the test compounds are reported in a separate paper by Ginman et al.
[<i>J. Med. Chem.</i> <b>2013</b>, <i>56</i>, 4181–4205]. The affinity predictions are described in detail
by Roos et al. [<i>J. Chem. Inf.</i> <b>2014</b>,
DOI: 10.1021/ci400374z]
