Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.
The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the alpha4beta2 potentiator mechanism in animal models of disease.
Albrecht
Brian K
BK
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA, USA. brian.albrecht@constellationpharma.com
Berry
Virginia
V
Boezio
Alessandro A
AA
Cao
Lei
L
Clarkin
Kristie
K
Guo
Wenhong
W
Harmange
Jean-Christophe
JC
Hierl
Markus
M
Huang
Liyue
L
Janosky
Brett
B
Knop
Johannes
J
Malmberg
Annika
A
McDermott
Jeff S
JS
Nguyen
Hung Q
HQ
Springer
Stephanie K
SK
Waldon
Daniel
D
Woodin
Katrina
K
McDonough
Stefan I
SI
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D006801:Humans; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship
D018722:Nicotinic Agonists; D010880:Piperidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2