1372186-95-2Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors - Part 2
Yukawa, Tomoya,Fujimori, Ikuo,Kamei, Taku,Nakada, Yoshihisa,Sakauchi, Nobuki,Yamada, Masami,Ohba, Yusuke,Ueno, Hiroyuki,Takiguchi, Maiko,Kuno, Masako,Kamo, Izumi,Nakagawa, Hideyuki,Fujioka, Yasushi,Igari, Tomoko,Ishichi, Yuji,Tsukamoto, Tetsuya
, p. 3207 - 32174 (2016/07/06)
Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H3)methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.
Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor
Fujimori, Ikuo,Yukawa, Tomoya,Kamei, Taku,Nakada, Yoshihisa,Sakauchi, Nobuki,Yamada, Masami,Ohba, Yusuke,Takiguchi, Maiko,Kuno, Masako,Kamo, Izumi,Nakagawa, Hideyuki,Hamada, Teruki,Igari, Tomoko,Okuda, Teruaki,Yamamoto, Satoshi,Tsukamoto, Tetsuya,Ishichi, Yuji,Ueno, Hiroyuki
, p. 5000 - 5014 (2015/08/03)
Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.
HETEROCYCLIC COMPOUNDS
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, (2012/04/18)
Provided is a compound having a monoamine reuptake inhibitory activity, which is represented by the formula (I) wherein ring A is an optionally substituted 6-membered aromatic ring, ring B is the substituents on ring A are optionally bonded to form, together with ring A, an optionally substituted 9- or 10-membered aromatic fused ring, and other symbols are as defined in the specification, or a salt thereof.
