Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein

J Med Chem. 2010 Sep 23;53(18):6572-83. doi: 10.1021/jm1002556.

Abstract

Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 100 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Animals
  • Dipeptidases / antagonists & inhibitors
  • Dipeptidyl-Peptidase IV Inhibitors
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
  • Endopeptidases
  • Gelatinases / antagonists & inhibitors*
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Pyrrolidonecarboxylic Acid / analogs & derivatives*
  • Pyrrolidonecarboxylic Acid / chemical synthesis*
  • Pyrrolidonecarboxylic Acid / pharmacokinetics
  • Pyrrolidonecarboxylic Acid / pharmacology
  • Serine Endopeptidases
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Amides
  • Dipeptidyl-Peptidase IV Inhibitors
  • Membrane Proteins
  • Endopeptidases
  • Dipeptidases
  • DPP9 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • dipeptidyl peptidase II
  • DPP8 protein, human
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases
  • Pyrrolidonecarboxylic Acid