title: From hit to lead. Analyzing structure-profile relationships.
abstract: Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.
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: D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D003627:Data Interpretation, Statistical; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D011956:Receptors, Cell Surface