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Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain.
Chem Pharm Bull (Tokyo). 2020; 68(7):653-663.CP

Abstract

The discovery of a novel class of state-dependent voltage-gated sodium channel (NaV)1.7 inhibitors is described. By the modification of amide or urethane bond in NaV1.7 blocker III, structure-activity relationship studies that led to the identification of novel NaV1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV1.7 without NaV1.1, NaV1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 μM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED50: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).

Authors+Show Affiliations

R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.Daiichi Sankyo RD Novare Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.R&D Division, Daiichi Sankyo Co., Ltd.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32612000

Citation

Tanaka, Kyosuke, et al. "Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain." Chemical & Pharmaceutical Bulletin, vol. 68, no. 7, 2020, pp. 653-663.
Tanaka K, Kobayashi H, Suzuki S, et al. Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain. Chem Pharm Bull. 2020;68(7):653-663.
Tanaka, K., Kobayashi, H., Suzuki, S., Shibuya, S., Kimoto, H., Domon, Y., Kubota, K., Kitano, Y., Yokoyama, T., Shimizugawa, A., Koishi, R., Fujiwara, C., Asano, D., & Shinozuka, T. (2020). Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain. Chemical & Pharmaceutical Bulletin, 68(7), 653-663. https://doi.org/10.1248/cpb.c20-00126
Tanaka K, et al. Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain. Chem Pharm Bull. 2020;68(7):653-663. PubMed PMID: 32612000.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain. AU - Tanaka,Kyosuke, AU - Kobayashi,Hiroyuki, AU - Suzuki,Sayaka, AU - Shibuya,Satoshi, AU - Kimoto,Hiroko, AU - Domon,Yuki, AU - Kubota,Kazufumi, AU - Kitano,Yutaka, AU - Yokoyama,Tomihisa, AU - Shimizugawa,Akiko, AU - Koishi,Ryuta, AU - Fujiwara,Chie, AU - Asano,Daigo, AU - Shinozuka,Tsuyoshi, PY - 2020/7/3/entrez KW - central nervous system (CNS) side effect KW - pain KW - quinolone KW - urethane KW - voltage-gated sodium channel SP - 653 EP - 663 JF - Chemical & pharmaceutical bulletin JO - Chem. Pharm. Bull. VL - 68 IS - 7 N2 - The discovery of a novel class of state-dependent voltage-gated sodium channel (NaV)1.7 inhibitors is described. By the modification of amide or urethane bond in NaV1.7 blocker III, structure-activity relationship studies that led to the identification of novel NaV1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV1.7 without NaV1.1, NaV1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 μM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED50: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold). SN - 1347-5223 UR - https://www.unboundmedicine.com/medline/citation/32612000/Discovery_of_a_Novel_Class_of_State-Dependent_NaV1.7_Inhibitors_for_the_Treatment_of_Neuropathic_Pain L2 - https://dx.doi.org/10.1248/cpb.c20-00126 DB - PRIME DP - Unbound Medicine ER -
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