Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor
| Autor: | Tomihisa Yokoyama, Sakiko Takahashi, Kiyoshi Takasuna, Noriyuki Hayashi, Hiroyuki Kobayashi, Ryuta Koishi, Chie Fujiwara, Eri Tokumaru, Yasuyuki Abe, Kyosuke Tanaka, Sayaka Suzuki, Kazufumi Kubota, Daigo Asano, Narayan Karanjule, Tsuyoshi Shinozuka, Masahiro Inoue, Hiroko Kimoto, Tsuda Toshifumi, Yutaka Kitano, Kiyono Ueda, Toshiyuki Watanabe, Yuki Domon, Tomoko Sakakura, Akiko Shimizugawa |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
CYP3A4 Sulfonamide (medicine) Glutathione Pharmacology 01 natural sciences In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound chemistry In vivo Drug Discovery NAV1 medicine Molecular Medicine Moiety Drug toxicity 030304 developmental biology medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 63:10204-10220 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile. |
| Databáze: | OpenAIRE |
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