title: Towards a KCC2 blocker pharmacophore model.
abstract: A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.
authors.affiliation: UCB Pharma, UCB NewMedicines, Chemin du Foriest, B-1420 Braine-L'Alleud, Belgium. florence.lebon@ucb.com
authors.forename: Florence
authors.initials: F
authors.lastname: Lebon
authors.forename: Cécile
authors.initials: C
authors.lastname: Pégurier
authors.forename: Marie
authors.initials: M
authors.lastname: Ledecq
authors.forename: Benoit
authors.initials: B
authors.lastname: Mathieu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bosman
authors.forename: Anne
authors.initials: A
authors.lastname: Frycia
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lengelé
authors.forename: Kashinath
authors.initials: K
authors.lastname: Dhurke
authors.forename: Ananda Kumar
authors.initials: AK
authors.lastname: Kanduluru
authors.forename: Stéphane
authors.initials: S
authors.lastname: Meunier
authors.forename: Alain
authors.initials: A
authors.lastname: Wagner
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
authors.forename: Laurent
authors.initials: L
authors.lastname: Provins
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005665:Furosemide / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014961:X-Ray Diffraction; D000096922:K Cl- Cotransporters
chemical_list: D000927:Anticonvulsants; D005665:Furosemide; D026902:Potassium Channel Blockers; D011392:Proline; D027981:Symporters; D000096922:K Cl- Cotransporters