Abstract
Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer’s disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.
Highlights
Alzheimer’s disease (AD), characterized by the slow but inexorable loss of memory and cognition, is affecting nearly 30 million people worldwide [1]
Finding novel compounds as starting points for lead optimization is a major challenge in drug discovery
As demonstrated in many drug discovery projects, the fragment-based drug design approach has its strengths in obtaining drug candidates with a good PK profile, because the starting fragment has large room for further optimization of both the potency and the pharmacokinetic properties
Summary
Alzheimer’s disease (AD), characterized by the slow but inexorable loss of memory and cognition, is affecting nearly 30 million people worldwide [1]. The amyloid β-peptide (Aβ), usually containing 40–42 amino acids, is derived from the β-amyloid precursor protein (APP) by subsequent proteolyses processed by β-site cleaving enzyme (BACE1) and γ-secretase [4,5] This amyloid hypothesis is embraced by many researchers, and considerable efforts have been devoted to develop new medicines to cure, if not at least halt, the progress of the disease in AD patients [6,7]. Astex applied their unique FBDD platform to BACE1, obtaining several fragment hits containing an aminopyridine motif [23]. They further carried out the lead optimization which led to a potent compound with an IC50 value of about 0.69 μM. We hope the results presented here can stimulate other researchers to develop new BACE1 inhibitors for AD treatment
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