Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors

J Med Chem. 2004 Jul 15;47(15):3730-43. doi: 10.1021/jm0306374.


We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide 8c.

MeSH terms

  • Adenosine Deaminase / chemistry
  • Adenosine Deaminase Inhibitors*
  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Animals
  • Crystallography, X-Ray
  • Drug Design
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Male
  • Models, Molecular
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Urea / chemistry


  • 1-(4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl)imidazole-4-carboxamide
  • Adenosine Deaminase Inhibitors
  • Amides
  • Imidazoles
  • Indoles
  • Urea
  • Adenosine Deaminase

Associated data

  • PDB/1O5R
  • PDB/1QXL
  • PDB/1UML