728880-26-0Relevant academic research and scientific papers
Discovery of potent iminoheterocycle BACE1 inhibitors
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
, p. 5455 - 5459 (2015/01/08)
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.
Discovery of cyclic acylguanidines as highly potent and selective β-site amyloid cleaving enzyme (BACE) inhibitors: Part I - Inhibitor design and validation
Zhu, Zhaoning,Sun, Zhong-Yue,Ye, Yuanzan,Voigt, Johannes,Strickland, Corey,Smith, Elizabeth M.,Cumming, Jared,Wang, Lingyan,Wong, Jesse,Wang, Yu-Sen,Wyss, Daniel F.,Chen, Xia,Kuvelkar, Reshma,Kennedy, Matthew E.,Favreau, Leonard,Parker, Eric,McKittrick, Brian A.,Stamford, Andrew,Czarniecki, Michael,Greenlee, William,Hunter, John C.
experimental part, p. 951 - 965 (2010/07/16)
A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180° in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.
Antihypertensive 5-amino-4-hydroxyvaleryl derivatives substituted by sulphur-containing groups
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, (2008/06/13)
Compounds of the formula STR1 in which R1 represents acyl substituted by a thio, sulphinyl or sulphonyl group, A represents an optionally N-alkylated α-amino acid residue that is bonded N-terminally to R1 and C-terminally to the grou
