Discovery of potent iminoheterocycle BACE1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2014-12, Vol.24 (23), p.5455-5459
• Main Authors: Caldwell, John P., Mazzola, Robert D., Durkin, James, Chen, Joseph, Chen, Xia, Favreau, Leonard, Kennedy, Matthew, Kuvelkar, Reshma, Lee, Julie, McHugh, Nansie, McKittrick, Brian, Orth, Peter, Stamford, Andrew, Strickland, Corey, Voigt, Johannes, Wang, Liyang, Zhang, Lili, Zhang, Qi, Zhu, Zhaoning
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer’s disease; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Amyloid Precursor Protein Secretases - therapeutic use; Animals; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Aspartic Acid Endopeptidases - therapeutic use; Aspartyl protease inhibitors; BACE; Drug Design; Drug Discovery; Models, Molecular; Molecular Structure; Rats; Structure-Activity Relationship; Structure-based drug design; β-Secretase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.10.006

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. [Display omitted] 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.