title: From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.
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.
authors.affiliation: Department of Chemistry, CEREP, 1 rue du Pr. Calmette, F-59000 Lille, France. rpoulain@phare.univ-lille2.fr
authors.forename: R
authors.initials: R
authors.lastname: Poulain
authors.forename: D
authors.initials: D
authors.lastname: Horvath
authors.forename: B
authors.initials: B
authors.lastname: Bonnet
authors.forename: C
authors.initials: C
authors.lastname: Eckhoff
authors.forename: B
authors.initials: B
authors.lastname: Chapelain
authors.forename: M C
authors.initials: MC
authors.lastname: Bodinier
authors.forename: B
authors.initials: B
authors.lastname: Déprez
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011869:Radioligand Assay; D051381:Rats; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C438589:2-(8-((6-chlorobenzo(1,3)dioxol-5-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro(4.5)dec-3-yl)-N-methylacetamide; D007093:Imidazoles; D008024:Ligands; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds