Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
Sams
Anette G
AG
Medicinal Chemistry Research, Lundbeck Research Denmark, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. anette.sams@leo-pharma.com
Hentzer
Morten
M
Mikkelsen
Gitte K
GK
Larsen
Krestian
K
Bundgaard
Christoffer
C
Plath
Niels
N
Christoffersen
Claus T
CT
Bang-Andersen
Benny
B
D000494:Allosteric Regulation; D000818:Animals; D044482:Benzeneacetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D013329:Structure-Activity Relationship
D044482:Benzeneacetamides; D048588:Benzoxazines; C552337:N-(1-(3-(3-oxo-2,3-dihydrobenzo(1,4)oxazin-4-yl)propyl)piperidin-4-yl)-2-phenylacetamide; D018697:Nootropic Agents; D010078:Oxazines; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D002118:Calcium