Journal : J. Med. Chem.
Title : From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.
Year : 2001
Volume : 44
Issue : 21
First Page : 3378
Last Page : 3390
Authors : Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Déprez B.
Abstract : 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.
