Synthesis and SAR of 4-aminocyclopentapyrrolidines as N-type Ca2+ channel blockers with analgesic activity

• Published in: Bioorganic & medicinal chemistry 2012-07, Vol.20 (13), p.4128-4139
• Main Authors: Beebe, Xenia, Darczak, Daria, Henry, Rodger F., Vortherms, Timothy, Janis, Richard, Namovic, Marian, Donnelly-Roberts, Diana, Kage, Karen L., Surowy, Carol, Milicic, Ivan, Niforatos, Wende, Swensen, Andrew, Marsh, Kennan C., Wetter, Jill M., Franklin, Pamela, Baker, Scott, Zhong, Chengmin, Simler, Gricelda, Gomez, Erica, Boyce-Rustay, Janel M., Zhu, Chang Z., Stewart, Andrew O., Jarvis, Michael F., Scott, Victoria E.
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - pharmacology; Acetamides - therapeutic use; Analgesic activity; analgesic effect; Analgesics; Analgesics - chemical synthesis; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Calcium; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Calcium channels; Calcium channels (L-type); Calcium channels (N-type); Calcium Channels, N-Type - chemistry; Calcium Channels, N-Type - metabolism; chemistry; Disease Models, Animal; Electrophysiological recording; Enantiomers; Enantioselective synthesis; Inflammation; L-type calcium channel; Male; Medical sciences; N-tert-Butyl sulfonamide; N-type calcium channel; Neuropharmacology; pain; Pain - drug therapy; Pain perception; Pharmacology. Drug treatments; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Rats; Rats, Sprague-Dawley; SAR; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.04.057

A novel 4-aminocyclopentapyrrolidine series of N-type Ca2+ 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 Ca2+ channels. N-type Ca2+ channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca2+ channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.