AMP deaminase inhibitors. 5. Design, synthesis, and SAR of a highly potent inhibitor series

J Med Chem. 2001 Feb 15;44(4):613-8. doi: 10.1021/jm000355t.

Abstract

A highly potent AMP deaminase (AMPDA) inhibitor series was discovered by replacing the N3 substitutents of the two lead AMPDA inhibitor series with a conformationally restricted group. The most potent compound, 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (24b), represents a 10- to 250-fold enhancement in AMPDA inhibitory potency without loss in the enzyme specificity. The potency of the inhibitor 24b (AMPDA K(i) = 0.002 microM) is 10(5)-fold lower than the Km for the substrate AMP. It represents the most potent nonnucleotide AMPDA inhibitor known.

MeSH terms

  • AMP Deaminase / antagonists & inhibitors*
  • AMP Deaminase / chemistry
  • Adenosine Deaminase / chemistry
  • Adenosine Deaminase Inhibitors
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Cattle
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Structure-Activity Relationship

Substances

  • 3-(2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl)-3,6,7,8-tetrahydroimidazo(4,5-d)(1,3)diazepin-8-ol
  • Adenosine Deaminase Inhibitors
  • Azepines
  • Enzyme Inhibitors
  • Imidazoles
  • Adenosine Deaminase
  • AMP Deaminase