Design and synthesis of inhibitors of adenosine and AMP deaminases.
Nucleosides and nucleotides which are able to undergo covalent hydration in the aglycone ring system are potential inhibitors of the enzymes adenosine deaminase (ADA) and AMP deaminase, respectively. Calculations of the enthalpy of covalent hydration and of enzyme binding energy have been used to design new inhibitors of ADA. The ribosyl triazolotriazine 16, which was synthesized as a result of these calculations, exists predominantly as the covalent hydrate 18 in water and is a potent inhibitor of mammalian ADA (IC(50) 50 nM).
Bojack
G
G
Aventis CropScience GmbH, Werk Höchst, G 836, D-65926 Frankfurt am Main, Germany.
Earnshaw
C G
CG
Klein
R
R
Lindell
S D
SD
Lowinski
C
C
Preuss
R
R
D000659:AMP Deaminase / Q000037:antagonists & inhibitors*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D002151:Calorimetry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008322:Mammals; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D009705:Nucleosides; D009711:Nucleotides; D000659:AMP Deaminase