From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.
J Med Chem
; 44(21): 3378-90, 2001 Oct 11.
Article
in En
| MEDLINE
| ID: mdl-11585443
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Spiro Compounds
/
Receptors, Opioid, mu
/
Imidazoles
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2001
Type:
Article
Affiliation country:
France