904686-53-9Relevant academic research and scientific papers
Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors
Malamas, Michael S.,Barnes, Keith,Hui, Yu,Johnson, Matthew,Lovering, Frank,Condon, Jeff,Fobare, William,Solvibile, William,Turner, Jim,Hu, Yun,Manas, Eric S.,Fan, Kristi,Olland, Andrea,Chopra, Rajiv,Bard, Jonathan,Pangalos, Menelas N.,Reinhart, Peter,Robichaud, Albert J.
, p. 2068 - 2073 (2010)
The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.
