title: A new pyridazine series of GABAA alpha5 ligands.
abstract: Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA alpha5 inverse agonists, made it an attractive molecule for further exploration. This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, United Kingdom. monique_vanniel@merck.com
authors.forename: Monique B
authors.initials: MB
authors.lastname: van Niel
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilson
authors.forename: Charles H
authors.initials: CH
authors.lastname: Adkins
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Clarke
authors.forename: Stephen
authors.initials: S
authors.lastname: Fletcher
authors.forename: Ute
authors.initials: U
authors.lastname: Gerhard
authors.forename: Mark M
authors.initials: MM
authors.lastname: Mackey
authors.forename: Sallie
authors.initials: S
authors.lastname: Malpas
authors.forename: Karen
authors.initials: K
authors.lastname: Maubach
authors.forename: Robert
authors.initials: R
authors.lastname: Newman
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Gopalan V
authors.initials: GV
authors.lastname: Pillai
authors.forename: Peter B
authors.initials: PB
authors.lastname: Simpson
authors.forename: Steven R
authors.initials: SR
authors.lastname: Thomas
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000502:physiology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D021122:Protein Subunits; D011724:Pyridazines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins