title: Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA, USA. brian.albrecht@constellationpharma.com
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Virginia
authors.initials: V
authors.lastname: Berry
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.forename: Kristie
authors.initials: K
authors.lastname: Clarkin
authors.forename: Wenhong
authors.initials: W
authors.lastname: Guo
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Markus
authors.initials: M
authors.lastname: Hierl
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: Brett
authors.initials: B
authors.lastname: Janosky
authors.forename: Johannes
authors.initials: J
authors.lastname: Knop
authors.forename: Annika
authors.initials: A
authors.lastname: Malmberg
authors.forename: Jeff S
authors.initials: JS
authors.lastname: McDermott
authors.forename: Hung Q
authors.initials: HQ
authors.lastname: Nguyen
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Springer
authors.forename: Daniel
authors.initials: D
authors.lastname: Waldon
authors.forename: Katrina
authors.initials: K
authors.lastname: Woodin
authors.forename: Stefan I
authors.initials: SI
authors.lastname: McDonough
mesh_terms: 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
chemical_list: D018722:Nicotinic Agonists; D010880:Piperidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2