4r91
BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(cyclopentylamino)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminiumBACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(cyclopentylamino)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium
Structural highlights
Publication Abstract from PubMedThe 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 Abeta40 levels upon subcutaneous and oral administration to rats. Discovery of potent iminoheterocycle BACE1 inhibitors.,Caldwell JP, Mazzola RD, 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 Bioorg Med Chem Lett. 2014 Oct 23;24(23):5455-5459. doi:, 10.1016/j.bmcl.2014.10.006. PMID:25455483[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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