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- Takashi Ogiyama, Koichi Yonezawa, Makoto Inoue, Toshihiro Watanabe, Yukihito Sugano, Takayasu Gotoh, Tetsuo Kiso, Akiko Koakutsu, Shuichiro Kakimoto, and Jun-Ichi Shishikura.
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: takashi.ogiyama@astellas.com.
- Bioorg. Med. Chem. 2015 Aug 1; 23 (15): 4624-4637.
AbstractN-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.Copyright © 2015 Elsevier Ltd. All rights reserved.
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