3L38

Bace1 in complex with the aminopyridine Compound 44

Summary for 3L38

• Entry DOI: 10.2210/pdb3l38/pdb
• Related: 3L3A
• Descriptor: Beta-secretase 1, 6-({2-(2-chlorophenyl)-5-[4-(pyrimidin-5-yloxy)phenyl]-1H-pyrrol-1-yl}methyl)pyridin-2-amine (3 entities in total)
• Functional Keywords: beta-secretase, bace-1, aminopyridine, inhibitor, aspartyl protease, disulfide bond, protease, transmembrane, zymogen, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46894.90

Authors

Olland, A.M.,Chopra, R. (deposition date: 2009-12-16, release date: 2010-04-28, Last modification date: 2024-10-09)

Primary citation

Malamas, M.S.,Barnes, K.,Hui, Y.,Johnson, M.,Lovering, F.,Condon, J.,Fobare, W.,Solvibile, W.,Turner, J.,Hu, Y.,Manas, E.S.,Fan, K.,Olland, A.,Chopra, R.,Bard, J.,Pangalos, M.N.,Reinhart, P.,Robichaud, A.J.
Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.
Bioorg.Med.Chem.Lett., 20:2068-2073, 2010

PubMed Abstract: The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-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.

PubMed: 20223661
DOI: 10.1016/j.bmcl.2010.02.075

Experimental method

X-RAY DIFFRACTION (2.1 Å)