Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, Copenhagen-Valby, Denmark. anette.sams@leo-pharma.com
Anette Graven
AG
Sams
Krestian
K
Larsen
Gitte Kobberøe
GK
Mikkelsen
Morten
M
Hentzer
Claus Tornby
CT
Christoffersen
Klaus Gjervig
KG
Jensen
Kristen
K
Frederiksen
Benny
B
Bang-Andersen
D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008024:Ligands; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D017448:Receptors, Dopamine D2