Rational design of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors: predicting enzyme conformational change and metabolism

J Med Chem. 2005 Jul 28;48(15):4750-3. doi: 10.1021/jm050413g.

Abstract

From metabolic considerations and prediction of an inhibitor-induced conformational change, novel adenosine deaminase (ADA) inhibitors with improved activities and oral bioavailability have been developed on the basis of our originally designed non-nucleoside ADA inhibitors. They demonstrated in vivo efficacy in models of inflammation and lymphoma. Furthermore, X-ray crystal structure analysis has revealed a novel induced fit to ADA.

MeSH terms

  • Adenosine Deaminase / chemistry
  • Adenosine Deaminase / metabolism
  • Adenosine Deaminase Inhibitors*
  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology
  • Biological Availability
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Mice
  • Mice, SCID
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Protein Conformation
  • Rats
  • Structure-Activity Relationship
  • U937 Cells
  • Xenograft Model Antitumor Assays

Substances

  • Adenosine Deaminase Inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Benzoxazoles
  • Imidazoles
  • Adenosine Deaminase