The Discovery of Pyridone and Pyridazone Heterocycles as γ-Secretase Modulators.

A series of novel pyridazone and pyridone compounds as γ-secretase modulators were discovered. Starting from the initial lead, structure-activity relationship studies were carried out in which an internal hydrogen bond was introduced to conformationally fix the side chain, and compounds with improved in vitro Aβ42 inhibition activity and good Aβtotal/Aβ42 selectivity were quickly discovered. Compound 35 displayed very good in vitro activity and excellent selectivity with good in vivo efficacy in both CRND8 mouse and nontransgenic rat models. This compound displayed a good overall profile in terms of rat pharmacokinetics and ancillary profile. No abnormal behavior and side effects were observed in all of the studies.