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Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of β-secretase (BACE).
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Nov 15; Vol. 21 (22), pp. 6916-24. Date of Electronic Publication: 2011 Jun 30. - Publication Year :
- 2011
-
Abstract
- The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Alzheimer Disease drug therapy
Alzheimer Disease enzymology
Animals
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacokinetics
Lactams chemical synthesis
Lactams pharmacokinetics
Mice
Models, Molecular
Rats
Structure-Activity Relationship
Amyloid Precursor Protein Secretases antagonists & inhibitors
Amyloid Precursor Protein Secretases metabolism
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Lactams chemistry
Lactams pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 21782431
- Full Text :
- https://doi.org/10.1016/j.bmcl.2011.06.109