From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands

J Med Chem. 2001 Oct 11;44(21):3378-90. doi: 10.1021/jm010877o.


Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism
  • Combinatorial Chemistry Techniques
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • In Vitro Techniques
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Radioligand Assay
  • Rats
  • Receptors, Opioid, mu / chemistry
  • Receptors, Opioid, mu / metabolism*
  • Solubility
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / metabolism
  • Structure-Activity Relationship


  • 2-(8-((6-chlorobenzo(1,3)dioxol-5-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro(4.5)dec-3-yl)-N-methylacetamide
  • Imidazoles
  • Ligands
  • Receptors, Opioid, mu
  • Spiro Compounds