Exploring S1 plasticity and probing S1' subsite of mammalian aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors

Bioorg Med Chem. 2015 Jul 1;23(13):3192-207. doi: 10.1016/j.bmc.2015.04.066. Epub 2015 May 1.

Abstract

In order to probe the S1 and S1' mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with Ki values in the nanomolar range.

Keywords: Aminopeptidase N inhibitors; Cancer; Racemic 1- or 4-substituted aminobenzocycloheptenone derivatives; Suzuki reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobenzoates / chemical synthesis*
  • Aminobenzoates / chemistry
  • Animals
  • Benzocycloheptenes / chemical synthesis*
  • Benzocycloheptenes / chemistry
  • CD13 Antigens / antagonists & inhibitors*
  • CD13 Antigens / chemistry
  • CD13 Antigens / isolation & purification
  • Kidney / chemistry
  • Kidney / enzymology
  • Molecular Docking Simulation
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine
  • Thermodynamics

Substances

  • Aminobenzoates
  • Benzocycloheptenes
  • Protease Inhibitors
  • CD13 Antigens