Synthesis and SAR of 4-aminocyclopentapyrrolidines as orally active N-type calcium channel inhibitors for inflammatory and neuropathic pain

Xenia Beebe; Clinton M Yeung; Daria Darczak; Shashank Shekhar; Timothy A Vortherms; Loan Miller; Ivan Milicic; Andrew M Swensen; Chang Z Zhu; Patricia Banfor; Jill M Wetter; Kennan C Marsh; Michael F Jarvis; Victoria E Scott; Michael R Schrimpf; Chih-Hung Lee

doi:10.1016/j.bmcl.2013.06.074

Synthesis and SAR of 4-aminocyclopentapyrrolidines as orally active N-type calcium channel inhibitors for inflammatory and neuropathic pain

Bioorg Med Chem Lett. 2013 Sep 1;23(17):4857-61. doi: 10.1016/j.bmcl.2013.06.074. Epub 2013 Jul 4.

Authors

Xenia Beebe¹, Clinton M Yeung, Daria Darczak, Shashank Shekhar, Timothy A Vortherms, Loan Miller, Ivan Milicic, Andrew M Swensen, Chang Z Zhu, Patricia Banfor, Jill M Wetter, Kennan C Marsh, Michael F Jarvis, Victoria E Scott, Michael R Schrimpf, Chih-Hung Lee

Affiliation

¹ Neuroscience Research, AbbVie, 1 N Waukegan Road, North Chicago, IL 60064, United States. xenia.b.searle@abbvie.com

PMID: 23876987
DOI: 10.1016/j.bmcl.2013.06.074

Abstract

A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and HT-ADME properties provides 4-aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.

Keywords: Analgesia; Enantiomeric synthesis; Microsomal stability; N-type calcium channels; SAR.

MeSH terms

Administration, Oral
Analgesics / chemical synthesis
Analgesics / chemistry*
Analgesics / metabolism
Analgesics / therapeutic use*
Animals
Calcium Channel Blockers / chemical synthesis
Calcium Channel Blockers / chemistry*
Calcium Channel Blockers / metabolism
Calcium Channel Blockers / therapeutic use*
Calcium Channels, N-Type / metabolism*
Humans
Microsomes / metabolism
Neuralgia / drug therapy*
Rats
Structure-Activity Relationship

Substances

Analgesics
Calcium Channel Blockers
Calcium Channels, N-Type