A new pyridazine series of GABAA alpha5 ligands.
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.
van Niel
Monique B
MB
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, United Kingdom. monique_vanniel@merck.com
Wilson
Kevin
K
Adkins
Charles H
CH
Atack
John R
JR
Castro
José L
JL
Clarke
Dawn E
DE
Fletcher
Stephen
S
Gerhard
Ute
U
Mackey
Mark M
MM
Malpas
Sallie
S
Maubach
Karen
K
Newman
Robert
R
O'Connor
Desmond
D
Pillai
Gopalan V
GV
Simpson
Peter B
PB
Thomas
Steven R
SR
MacLeod
Angus M
AM
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
D008024:Ligands; D021122:Protein Subunits; D011724:Pyridazines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins