4R91

BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(cyclopentylamino)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium

Summary for 4R91

• Entry DOI: 10.2210/pdb4r91/pdb
• Related: 4R8Y 4R92 4R93 4R95
• Descriptor: Beta-secretase 1, L(+)-TARTARIC ACID, (2E,5R)-5-(2-cyclohexylethyl)-5-{[(1S,3R)-3-(cyclopentylamino)cyclohexyl]methyl}-2-imino-3-methylimidazolidin-4-one, ... (4 entities in total)
• Functional Keywords: aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 2
• Total formula weight: 93605.26

Authors

Orth, P.,Caldwell, J.P.,Strickland, C. (deposition date: 2014-09-03, release date: 2014-11-05, Last modification date: 2024-10-16)

Primary citation

Caldwell, J.P.,Mazzola, R.D.,Durkin, J.,Chen, J.,Chen, X.,Favreau, L.,Kennedy, M.,Kuvelkar, R.,Lee, J.,McHugh, N.,McKittrick, B.,Orth, P.,Stamford, A.,Strickland, C.,Voigt, J.,Wang, L.,Zhang, L.,Zhang, Q.,Zhu, Z.
Discovery of potent iminoheterocycle BACE1 inhibitors.
Bioorg.Med.Chem.Lett., 24:5455-5459, 2014

PubMed Abstract: The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats.

PubMed: 25455483
DOI: 10.1016/j.bmcl.2014.10.006

Experimental method

X-RAY DIFFRACTION (1.58 Å)