Yuji Ishichi

Yuji Ishichi; Eiji Kimura; Eiji Honda; Masato Yoshikawa; Takashi Nakahata; Yasuko Terao; Atsuko Suzuki; Takayuki Kawai; Yuuichi Arakawa; Hiroyuki Ohta; Naoyuki Kanzaki; Hideyuki Nakagawa; Jun Terauchi

A novel triple reuptake inhibitor with low potential of liabilities associated with cationic amphiphilic drug (CAD) was identified following an analysis of existing drugs. Low molecular weight (MW < ca. 300), low aromatic ring count (number = 1) and reduced lipophilicity (ClogP < 3.5) were hypothesized to be key factors to avoid the CAD associated liabilities (CYP2D6 inhibition, hERG inhibition and phospholipidosis). Based on the hypothesis, a series of piperidine compounds was designed with consideration of the common characteristic features of CNS drugs. Optimization of the side chain by adjusting overall lipophilicity suggested that incorporation of a methoxymethyl group could provide compounds with a balance of both potent reuptake inhibition and low liability potential. Compound (S)-3a showed a potent antidepressant-like effect in the mice tail suspension test (MED = 10 mg/kg, p.o.), proportional monoamine transporter occupancies and enhancement of monoamine concentrations in mouse prefrontal cortex.

Eiji Honda; Yuji Ishichi; Eiji Kimura; Masato Yoshikawa; Naoyuki Kanzaki; Hideyuki Nakagawa; Yasuko Terao; Atsuko Suzuki; Takayuki Kawai; Yuuichi Arakawa; Hiroyuki Ohta; Jun Terauchi

A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.

Ikuo Fujimori; Tomoya Yukawa; Taku Kamei; Yoshihisa Nakada; Nobuki Sakauchi; Masami Yamada; Yusuke Ohba; Maiko Takiguchi; Masako Kuno; Izumi Kamo; Hideyuki Nakagawa; Teruki Hamada; Tomoko Igari; Teruaki Okuda; Satoshi Yamamoto; Tetsuya Tsukamoto; Yuji Ishichi; Hiroyuki Ueno

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.

Michiyo Mochizuki; Takuto Kojima; Katsumi Kobayashi; Etsuo Kotani; Yuji Ishichi; Naoyuki Kanzaki; Hideyuki Nakagawa; Teruaki Okuda; Yohei Kosugi; Takahiko Yano; Yuu Sako; Maiko Tanaka; Kazuyoshi Aso

Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50=4.1nM), in vitro antagonistic activity (IC50=44nM), and slow dissociation from the CRF1 receptor. Orally administered compound 24d (6-24μmol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d.

Hideaki Natsugari; Yoshinori Ikeura; Yutaka Kiyota; Yuji Ishichi; Takenori Ishimaru; Osamu Saga; Hideo Shirafuji; Toshimasa Tanaka; Izumi Kamo

Hideaki Natsugari; Yoshinori Ikeura; Izumi Kamo; Takenori Ishimaru; Yuji Ishichi; Akira Fujishima; Toshimasa Tanaka; Fumiko Kasahara; Mitsuru Kawada; Takayuki Doi

Yoshinori Ikeura; Yuji Ishichi; Toshimasa Tanaka; Akira Fujishima; Mika Murabayashi; Mitsuru Kawada; Takenori Ishimaru; Izumi Kamo; Takayuki Doi; Hideaki Natsugari

Yuji Ishichi; Yoshinori Ikeura; Hideaki Natsugari

Yuji Ishihara; Takayuki Doi; Hiroshi Nagabukuro; Yuji Ishichi

Yuji Ishihara; Yuji Ishichi; Takayuki Doi; Hiroshi Nagabukuro; Naoyuki Kanzaki; Motoki Ikeuchi