P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K

An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an e...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-08, Vol.15 (15), p.3540-3546
Main Authors: BARRETT, David G, BONCEK, Virginia M, PAYNE, J. Alan, RAY, John A, SAMANO, Vicente, SHEWCHUK, Lisa M, TAVARES, Francis X, WELLS-KNECHT, Kevin J, WILLARD, Derril H, WRIGHT, Lois L, ZHOU, Hui-Qiang Q, CATALANO, John G, DEATON, David N, HASSELL, Anne M, JURGENSEN, Cynthia H, LONG, Stacey T, MCFADYEN, Robert B, MILLER, Aaron B, MILLER, Larry R
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - pharmacokinetics
Amides - pharmacology
Animals
Binding Sites
Biological and medical sciences
Biological Availability
Bone Resorption - drug therapy
Bone Resorption - metabolism
Bones, joints and connective tissue. Antiinflammatory agents
Cathepsin K
Cathepsins - antagonists & inhibitors
Cathepsins - chemistry
Cysteine Proteinase Inhibitors - chemical synthesis
Cysteine Proteinase Inhibitors - pharmacokinetics
Cysteine Proteinase Inhibitors - pharmacology
Disease Models, Animal
Hypocalcemia - drug therapy
Hypocalcemia - metabolism
Ketones - chemical synthesis
Ketones - pharmacokinetics
Ketones - pharmacology
Medical sciences
Pharmacology. Drug treatments
Rats
Rats, Wistar
Solubility
Structure-Activity Relationship
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Summary:An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.05.062