Novel, potent P2–P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2006-03, Vol.16 (6), p.1735-1739
• Main Authors: Barrett, David G., Catalano, John G., Deaton, David N., Hassell, Anne M., Long, Stacey T., Miller, Aaron B., Miller, Larry R., Ray, John A., Samano, Vicente, Shewchuk, Lisa M., Wells-Knecht, Kevin J., Willard, Derril H., Wright, Lois L.
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - pharmacokinetics; Amides - pharmacology; Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cathepsin K; Cathepsins - antagonists & inhibitors; Cathepsins - chemistry; Crystallography, X-Ray; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - pharmacokinetics; Cysteine Proteinase Inhibitors - pharmacology; Humans; Inhibitor; Inhibitory Concentration 50; Ketoamide; Ketones - chemical synthesis; Ketones - pharmacokinetics; Ketones - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Osteoporosis; Pharmacology. Drug treatments; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Serine Proteinase Inhibitors; Structure-Activity Relationship; Synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.11.101

Starting from a potent pantolactone ketoamide cathepsin K inhibitor derived from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S3 subsite of cathepsin K. Manipulation of P3 and P1′ groups afforded potent inhibitors with drug-like properties Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S3 subsite of cathepsin K. Manipulation of P3 and P1′ groups afforded potent inhibitors with drug-like properties.