904686-29-9Relevant 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.
scheme or table, p. 2068 - 2073 (2010/06/19)
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.
Amino-pyridines as inhibitors of beta-secretase
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Page/Page column 28-29, (2008/06/13)
The present invention provides an amino-pyridine compound of formula I The present invention also provides methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles.
