Exploration of the P2-P3 SAR of aldehyde cathepsin K inhibitors

The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s bet...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-07, Vol.14 (13), p.3425-3429
Main Authors: BORES, Eric E, DEATON, David N, WRIGHT, Lois L, HASSELL, Anne M, MCFADYEN, Robert B, MILLER, Aaron B, MILLER, Larry R, PAULICK, Margot G, SHEWCHUK, Lisa M, THOMPSON, James B, WILLARD, Derril H
Format: Article
Language:English
Subjects:
Aldehydes - chemistry
Aldehydes - pharmacology
Binding Sites - drug effects
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Carbamates - chemistry
Cathepsin K
Cathepsins - antagonists & inhibitors
Humans
Inhibitory Concentration 50
Medical sciences
Norleucine - chemistry
Pharmacology. Drug treatments
Protease Inhibitors - chemical synthesis
Protease Inhibitors - pharmacology
Structure-Activity Relationship
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Summary:The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(04)00600-6