Based on the lead compounds 1 and 2, a series of novel BACE1 inhibitors were designed and synthesized,among which compound 9h exhibited a 60 fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD. The result also showed that the prop-2-yn-1-yloxy is a suitable fragment for modification of cyclic acylguanidine BACE1 inhibitors.
By taking compound 1 as a lead, a series of 5-cyclopropyl substituted cyclic acylguanidine compounds were designed and synthesized as BACE1 inhibitors, compound 4d exhibited 84-fold improved inhibition efficiency than lead compound 1. The diphenyl fragment at the P3 position and the substituents at the second phenyl ring were essential for the compounds to achieve improved inhibition efficiency. This SAR studies provides new insights into the design and synthesis of more promising BACE1 inhibitors for the potential treatment of AD.
Based on the lead compound 1 reported in literature, a series of novel BACE1 inhibitors were designed and synthesized, among which compound 11 exhibited a 14-fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD.
Jia-Kuo LiuWei GuXiao-Rui ChengJun-Ping ChengWen-Xia ZhouAi-Hua Nie
