| Alzheimer's disease(AD) has been one of the most severe neurodegenerative disorders of the elderly.More and more results proved thatβ-amyloid peptide(Aβ) is most likely to be the original and crucial factor of AD,BACE-1 is the rate-limiting catalytic step in the process of Aβgeneration.In the past few years,non-peptide BACE-1 inhibitors have become promising candidate in the field of discovery and development of AD therapeutic drugs.Through detailed study on the crystal structure of two lead compounds (2-amino-pyridine derivates 2-3,2-amino- methyl oxadiazole derivates 2-56)-BACE-1 complex,as well as the crystal,structure of OM99-2-BACE-1 complex., trisubstituted phenyl moiety in compound 2-3 was chosen as the skeleton,and 2-amino-thiazole,2-amino-benzoxazole and 2-amino-thiadiazine have been introduced to the phenyl ring separately according to the bioisostere principle,of which the amino group and heterocycle can form hydrogen bonds with the catalytic center of BACE-1. Aromatic B fragments were introduced in position 2 of the phenyl ring to reach the S2' pocket,while different aromatic heterocycles were introduced in position 5 of the phenyl ring to get good interaction with important hydrophobic pockets(S1,S3).Thus, a series of new amino heterocycle derivatives have been designed asβ-secretase inhibitors.Furthermore,according to the ring-open principle,semicarbazide moiety was used to replace amino heterocycle to get semicarbazide derivatives.All the 49 synthesized compounds were tested in vitro for their BACEl inhibitory activity,the result showed that,12 compounds exhibited more than 50%inhibition of BACE-1 in 20μM.Among them,2-amino-thiadiazine derivatives showed higher inhibitory activities than other series,and the most potent compoundⅢ-6 exhibits IC50 value as 9.9μM.The results of BBB penetration and cell uptake kinetics for compoundsⅢ-4,Ⅳ-9 andⅣ-19 revealed that these compounds were not the substrates of P-gp.
|
PDF Full Text Request