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

Bioorg Med Chem Lett. 2006 Mar 15;16(6):1735-9. doi: 10.1016/j.bmcl.2005.11.101. Epub 2006 Jan 11.

Abstract

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 S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.

Publication types

  • Comparative Study

MeSH terms

  • Amides* / chemical synthesis
  • Amides* / pharmacokinetics
  • Amides* / pharmacology
  • Binding Sites
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / chemistry
  • Crystallography, X-Ray
  • Cysteine Proteinase Inhibitors* / chemical synthesis
  • Cysteine Proteinase Inhibitors* / pharmacokinetics
  • Cysteine Proteinase Inhibitors* / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Ketones* / chemical synthesis
  • Ketones* / pharmacokinetics
  • Ketones* / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Pyrrolidines* / chemical synthesis
  • Pyrrolidines* / pharmacokinetics
  • Pyrrolidines* / pharmacology
  • Serine Proteinase Inhibitors
  • Structure-Activity Relationship

Substances

  • Amides
  • Cysteine Proteinase Inhibitors
  • Ketones
  • Pyrrolidines
  • Serine Proteinase Inhibitors
  • Cathepsins
  • CTSK protein, human
  • Cathepsin K
  • pyrrolidine