title: Synthesis and SAR of 4-aminocyclopentapyrrolidines as N-type Ca²⁺ channel blockers with analgesic activity.
abstract: A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, United States. xenia.b.searle@abbott.com
authors.forename: Xenia
authors.initials: X
authors.lastname: Beebe
authors.forename: Daria
authors.initials: D
authors.lastname: Darczak
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Timothy
authors.initials: T
authors.lastname: Vortherms
authors.forename: Richard
authors.initials: R
authors.lastname: Janis
authors.forename: Marian
authors.initials: M
authors.lastname: Namovic
authors.forename: Diana
authors.initials: D
authors.lastname: Donnelly-Roberts
authors.forename: Karen L
authors.initials: KL
authors.lastname: Kage
authors.forename: Carol
authors.initials: C
authors.lastname: Surowy
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.forename: Andrew
authors.initials: A
authors.lastname: Swensen
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Pamela
authors.initials: P
authors.lastname: Franklin
authors.forename: Scott
authors.initials: S
authors.lastname: Baker
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Gricelda
authors.initials: G
authors.lastname: Simler
authors.forename: Erica
authors.initials: E
authors.lastname: Gomez
authors.forename: Janel M
authors.initials: JM
authors.lastname: Boyce-Rustay
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Scott
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000737:chemistry* / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D010146:Pain / Q000188:drug therapy; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C575515:2,2-dicyclohexyl-N-(2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta(c)pyrrol-4-yl)acetamide; D000081:Acetamides; D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D011759:Pyrrolidines; C032519:pyrrolidine