Shin Iimura
Daiichi Sankyo
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Featured researches published by Shin Iimura.
Bioorganic & Medicinal Chemistry Letters | 2001
Shin Iimura; Kouichi Uoto; Satoru Ohsuki; Jun Chiba; Toshiharu Yoshino; Michio Iwahana; Takeshi Jimbo; Hirofumi Terasawa; Tsunehiko Soga
To improve cytotoxicity of 10-deoxy-10-C-morpholinoethyl docetaxel analogues against various tumor cell lines including resistant cells expressing P-glycoprotein (P-gp), we modified the 7-hydroxyl group to hydrophobic groups (methoxy, deoxy, 6,7-olefin, alpha-F, 7-beta-8-beta-methano, fluoromethoxy). Among these analogues, the 7-methoxy analogue showed the strongest cytotoxicity. This analogue showed potent activity against B16 melanoma BL6 in vivo by oral administration.
Journal of Medicinal Chemistry | 2009
Fumihito Muro; Shin Iimura; Yuuichi Sugimoto; Yoshiyuki Yoneda; Jun Chiba; Toshiyuki Watanabe; Masaki Setoguchi; Yutaka Iigou; Keiko Matsumoto; Atsushi Satoh; Gensuke Takayama; Tomoe Taira; Mika Yokoyama; Tohru Takashi; Atsushi Nakayama; Nobuo Machinaga
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
Journal of Medicinal Chemistry | 2016
Jean-Marc Lapierre; Sudharshan Eathiraj; David Vensel; Yanbin Liu; Cathy Bull; Susan Cornell-Kennon; Shin Iimura; Eugene Kelleher; Darin Kizer; Steffi Koerner; Sapna Makhija; Akihisa Matsuda; Magdi Moussa; Nivedita Namdev; Ronald E. Savage; Jeff Szwaya; Erika Volckova; Neil Westlund; Hui Wu; Brian S. Schwartz
The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
Bioorganic & Medicinal Chemistry Letters | 2010
Hiroki Shimizu; Shinji Tanaka; Tadashi Toki; Isao Yasumatsu; Toshihiko Akimoto; Kaoru Morishita; Tomonori Yamasaki; Takanori Yasukochi; Shin Iimura
Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity. The structure-activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compounds with IKKbeta was constructed.
Bioorganic & Medicinal Chemistry Letters | 2011
Hiroki Shimizu; Tomonori Yamasaki; Yoshiyuki Yoneda; Fumihito Muro; Tomoaki Hamada; Takanori Yasukochi; Shinji Tanaka; Tadashi Toki; Mika Yokoyama; Kaoru Morishita; Shin Iimura
We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.
Bioorganic & Medicinal Chemistry Letters | 2011
Hiroki Shimizu; Isao Yasumatsu; Tomoaki Hamada; Yoshiyuki Yoneda; Tomonori Yamasaki; Shinji Tanaka; Tadashi Toki; Mika Yokoyama; Kaoru Morishita; Shin Iimura
We have increased the potency of imidazo[1,2-b]pyridazine derivatives as IKKβ inhibitors with two strategies. One is to enhance the activity in cell-based assay by adjusting the polarity of molecules to improve permeability. Another is to increase the affinity for IKKβ by the introduction of additional substituents based on the hypothesis derived from an interaction model study. These improved compounds showed inhibitory activity of TNFα production in mice.
Bioorganic & Medicinal Chemistry | 2009
Fumihito Muro; Shin Iimura; Yoshiyuki Yoneda; Jun Chiba; Toshiyuki Watanabe; Masaki Setoguchi; Gensuke Takayama; Mika Yokoyama; Tohru Takashi; Atsushi Nakayama; Nobuo Machinaga
During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC(50)=19 nM) in VLA-4 inhibitory activity compared to 1 (IC(50)=1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50)=2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL=3.3 ml/min/kg, F=51%) in rats.
Bioorganic & Medicinal Chemistry | 2008
Fumihito Muro; Shin Iimura; Yoshiyuki Yoneda; Jun Chiba; Toshiyuki Watanabe; Masaki Setoguchi; Yutaka Iigou; Gensuke Takayama; Mika Yokoyama; Tohru Takashi; Atsushi Nakayama; Nobuo Machinaga
Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.
Bioorganic & Medicinal Chemistry | 2013
Masaki Setoguchi; Shin Iimura; Yuuichi Sugimoto; Yoshiyuki Yoneda; Jun Chiba; Toshiyuki Watanabe; Fumihito Muro; Yutaka Iigo; Gensuke Takayama; Mika Yokoyama; Tomoe Taira; Misato Aonuma; Tohru Takashi; Atsushi Nakayama; Nobuo Machinaga
We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.
Bioorganic & Medicinal Chemistry Letters | 1998
Kiyoshi Nakayama; Hirofumi Terasawa; Ikuo Mitsui; Satoru Ohsuki; Kouichi Uoto; Shin Iimura; Tsunehiko Soga
An alkylation method of docetaxel at the C-10 position has been established by a radical coupling reaction using a 10-xanthate derivative of 7-O-TES-10-deacetylbaccatin III and appropriate alkenes. In addition the cytotoxic activity of 10-alkylated docetaxel analogs was evaluated. Among these analogs, a derivative having a methoxycarbonyl group at the end of the alkyl moiety exhibited more potent cytotoxic activity than docetaxel.