A novel β ‐sheet breaker, RS‐0406, reverses amyloid β ‐induced cytotoxicity and impairment of long‐term potentiation in vitro

Fibril formation of amyloid β peptide (Aβ) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Aβ fibril is formed by a protein misfolding process in which intermolecular β‐sheet interactions become stabilized abnormally. Thus, to develop potential anti‐AD drugs, we screened an in‐house library to find compounds which have a profile as a β‐sheet breaker. We searched for a β‐sheet breaker profile in an in‐house library of approximately 113,000 compounds. From among the screening hits, we focused on N , N ′‐bis(3‐hydroxyphenyl)pyridazine‐3,6‐diamine (named RS‐0406), which had been newly synthesized in our laboratory. This compound (10–100 μg ml −1 ) was found to be capable of significantly inhibiting 25 μ M Aβ 1–42 fibrillogenesis and, furthermore, disassembling preformed Aβ 1–42 fibrils in vitro . We then investigated the effect of RS‐0406 on 111 n M Aβ 1–42 ‐induced cytotoxicity in primary hippocampal neurons, and found that 0.3–3 μg ml −1 RS‐0406 ameliorates the cytotoxicity. Moreover, 3 μg ml −1 RS‐0406 reversed 1 μ M Aβ 1–42 ‐induced impairment of long‐term potentiation in hippocampal slices. In this study, we have succeeded in identifying RS‐0406 which has potential to inhibit Aβ 1–42 fibrillogenesis, and to protect neurons against Aβ 1–42 ‐induced biological toxicity in vitro . These results suggest that RS‐0406 or one of the derivatives could become a therapeutic agent for AD patients.British Journal of Pharmacology (2002) 137 , 676–682. doi: 10.1038/sj.bjp.0704911