Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones

Bioorg Med Chem. 2018 Jul 23;26(12):3639-3653. doi: 10.1016/j.bmc.2018.05.044. Epub 2018 May 26.


A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.

Keywords: 1,4-Diazepan-7-one; KLK7 inhibitor; Serine protease; Species differences; Structure-based drug design.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Azepines / chemistry*
  • Azepines / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Kallikreins / antagonists & inhibitors
  • Kallikreins / metabolism*
  • Mice
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship


  • Azepines
  • Protease Inhibitors
  • KLK7 protein, human
  • Kallikreins
  • Klk7 protein, mouse