| Structural highlights
Publication Abstract from PubMed
The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.,Bowers S, Xu YZ, Yuan S, Probst GD, Hom RK, Chan W, Konradi AW, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR Bioorg Med Chem Lett. 2013 Apr 1;23(7):2181-6. doi: 10.1016/j.bmcl.2013.01.103., Epub 2013 Feb 4. PMID:23465612[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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References
- ↑ Bowers S, Xu YZ, Yuan S, Probst GD, Hom RK, Chan W, Konradi AW, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR. Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates. Bioorg Med Chem Lett. 2013 Apr 1;23(7):2181-6. doi: 10.1016/j.bmcl.2013.01.103., Epub 2013 Feb 4. PMID:23465612 doi:http://dx.doi.org/10.1016/j.bmcl.2013.01.103
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