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Discovery of a 1-isopropyltetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain.

Abstract
N-type calcium channel blockade is a promising therapeutic approach for the treatment of neuropathic pain. Starting from lead compound (S)-1, we focused our optimization efforts on potency for N-type calcium channel inhibition and improvement of CYP inhibition profile. 2-{[(1-Hydroxycyclohexyl)methyl]amino}-(1R)-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone oxalate ((R)-5r) was identified as a novel orally active small-molecule N-type calcium channel inhibitor with reduced CYP inhibition liability. Oral administration of (R)-5r improved mechanical allodynia in a spinal nerve ligation model of neuropathic pain in rats with an ED50 value of 2.5 mg/kg.
AuthorsTakashi Ogiyama, Koichi Yonezawa, Makoto Inoue, Toshihiro Watanabe, Yukihito Sugano, Takayasu Gotoh, Tetsuo Kiso, Akiko Koakutsu, Shuichiro Kakimoto, Jun-Ichi Shishikura
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 15 Pg. 4624-4637 (Aug 01 2015) ISSN: 1464-3391 [Electronic] England
PMID26071371 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Calcium Channel Blockers
  • Isoquinolines
Topics
  • Animals
  • Calcium Channel Blockers (administration & dosage, pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Humans
  • Isoquinolines (administration & dosage, pharmacology, therapeutic use)
  • Male
  • Mice
  • Neuralgia (drug therapy)
  • Rats
  • Rats, Sprague-Dawley

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