title: Discovery of novel tetrahydroisoquinoline derivatives as orally active N-type calcium channel blockers with high selectivity for hERG potassium channels.
abstract: N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: takashi.ogiyama@astellas.com.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogiyama
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Honda
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Gotoh
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kiso
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Koakutsu
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Kakimoto
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Shishikura
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D009437:Neuralgia / Q000188:drug therapy; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D051638:Ether-A-Go-Go Potassium Channels; D044005:Tetrahydroisoquinolines; D003577:Cytochrome P-450 Enzyme System
keywords: N-type calcium channel; Pain; hERG