Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions

A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high sel...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-10, Vol.14 (19), p.4897-4902
Main Authors: BARRETT, David G, CATALANO, John G, WRIGHT, Lois L, DEATON, David N, HASSELL, Anne M, LONG, Stacey T, MILLER, Aaron B, MILLER, Larry R, SHEWCHUK, Lisa M, WELLS-KNECHT, Kevin J, WILLARD, Derril H
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - pharmacokinetics
Amides - pharmacology
Binding Sites
Biological and medical sciences
Cathepsin K
Cathepsins - antagonists & inhibitors
Cathepsins - chemistry
Cysteine Proteinase Inhibitors - chemical synthesis
Humans
Medical sciences
Miscellaneous
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.07.031