- Design and synthesis of indoleamine 2,3-dioxygenase 1 inhibitors and evaluation of their use as anti-tumor agents
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Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC50 values of 0.3–0.5 μM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (～36% of hepatic blood flow), acceptable half-life (～4.6 h), and high oral bioavailability (～96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.
- Wen, Hui,Liu, Yuke,Wang, Shufang,Wang, Ting,Zhang, Gang,Chen, Xiaoguang,Li, Yan,Cui, Huaqing,Lai, Fangfang,Sheng, Li
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- Lithium tert-butoxide-mediated carboxylation reactions of unprotected indoles and pyrroles with carbon dioxide
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Unprotected indoles and pyrroles were found to undergo base-mediated carboxylation reactions under ambient pressure of carbon dioxide. It was found that this transition metal-free carboxylation reaction proceeded smoothly with the use of a large excess of LiOtBu.
- Yoo, Woo-Jin,Nguyen, Thanh V. Q.,Guiteras Capdevila, Montse,Kobayashi, Shu
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p. 1196 - 1204
(2015/04/21)
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- N -[6-(4-Butanoyl-5-methyl-1 H -pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1 H -indole-3-carboxamide (SAR216471), a Novel Intravenous and Oral, Reversible, and Directly Acting P2Y12 Antagonist
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In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.
- Boldron, Christophe,Besse, Angélina,Bordes, Marie-Fran?oise,Tissandié, Stéphanie,Yvon, Xavier,Gau, Benjamin,Badorc, Alain,Rousseaux, Tristan,Barré, Guillaume,Meneyrol, Jér?me,Zech, Gernot,Nazare, Marc,Fossey, Valérie,Pflieger, Anne-Marie,Bonnet-Lignon, Sandrine,Millet, Laurence,Briot, Christophe,Dol, Frédérique,Hérault, Jean-Pascal,Savi, Pierre,Lassalle, Gilbert,Delesque, Nathalie,Herbert, Jean-Marc,Bono, Fran?oise
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p. 7293 - 7316
(2015/01/08)
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- Base-mediated carboxylation of unprotected indole derivatives with carbon dioxide
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A simple and straightforward method for the preparation of indole-3-carboxylic acids was discovered through the direct carboxylation of indoles with atmospheric pressure of carbon dioxide (CO2) under basic conditions. The key for the reaction was found to be the use of a large excess of LiOtBu as a base to suppress the undesired decarboxylation side reaction.
- Yoo, Woo-Jin,Capdevila, Montse Guiteras,Du, Xiangwei,Kobayashi, Shu
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supporting information
p. 5326 - 5329,4
(2020/09/02)
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- NOVEL INDOL CARBOXYLIC ACID BISPYRIDYL CARBOXAMIDE DERIVATIVES, PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PREPARATION METHOD AND COMPOSITION CONTAINING THE SAME AS AN ACTIVE INGREDIENT
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Disclosed herein are a new indole carboxylic acid bispyridyl carboxamide derivative, a preparation method thereof, and a composition for prevention or treatment of obesity, urinary disorders, and CNS disorders, containing the same as an active ingredient. Because the indole carboxylic acid bispyridyl carboxamide derivatives according to the present invention have high affinity for 5-HT2c receptors, act selectively on the 5-HT2c receptors, the derivatives rarely have adverse effects caused by other receptors. Because the derivatives effectively inhibit serotonin activity, they may be useful for treatment or prevention of obesity; urinary disorders such as urinary incontinence, premature ejaculation, erectile dysfunction, and prostatic hyperplasia; CNS disorders such as depression, anxiety, concern, panic disorder, epilepsy, obsessive-compulsive disorder, migraine, sleep disorder, withdrawal from drug abuse, Alzheimer's disease, and schizophrenia, associated with 5-HT2c receptors.
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Page/Page column 11
(2009/10/21)
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- Novel indol carboxylic acid bispyridyl carboxamide derivatives as 5-HT2c receptor antagonists
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Disclosed herein are a new indole carboxylic acid bispyridyl carboxamide derivative, a preparation method thereof, and a composition for prevention or treatment of obesity, urinary disorders, and CNS disorders, containing the same as an active ingredient. Because the indole carboxylic acid bispyridyl carboxamide derivatives according to the present invention have high affinity for 5-HT2c receptors, act selectively on the 5-HT2c receptors, the derivatives rarely have adverse effects caused by other receptors. Because the derivatives effectively inhibit serotonin activity, they may be useful for treatment or prevention of obesity; urinary disorders such as urinary incontinence, premature ejaculation, erectile dysfunction, and prostatic hyperplasia; CNS disorders such as depression, anxiety, concern, panic disorder, epilepsy, obsessive-compulsive disorder, migraine, sleep disorder, withdrawal from drug abuse, Alzheimer's disease, and schizophrenia, associated with 5-HT2c receptors.
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Page/Page column 17
(2009/10/21)
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- NOVEL INDOL CARBOXYLIC ACID BISPYRIDYL CARBOXAMIDE DERIVATIVES, PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PREPARATION METHOD AND COMPOSITION CONTAINING THE SAME AS AN ACTIVE INGREDIENT
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Disclosed herein are a new indole carboxylic acid bispyridyl carboxamide derivative, a preparation method thereof, and a composition for prevention or treatment of obesity, urinary disorders, and CNS disorders, containing the same as an active ingredient. Because the indole carboxylic acid bispyridyl carboxamide derivatives according to the present invention have high affinity for 5-HT2c receptors, act selectively on the 5-HT2c receptors, the derivatives rarely have adverse effects caused by other receptors. Because the derivatives effectively inhibit serotonin activity, they may be useful for treatment or prevention of obesity; urinary disorders such as urinary incontinence, premature ejaculation, erectile dysfunction, and prostatic hyperplasia; CNS disorders such as depression, anxiety, concern, panic disorder, epilepsy, obsessive-compulsive disorder, migraine, sleep disorder, withdrawal from drug abuse, Alzheimer's disease, and schizophrenia, associated with 5-HT2c receptors.
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Page/Page column 29
(2009/11/29)
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- Synthesis and structure-activity relationship of 1H-indole-3-carboxylic acid pyridine-3-ylamides: A novel series of 5-HT2C receptor antagonists
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A novel series of 1H-indole-3-carboxylic acid pyridine-3-ylamides were synthesized and identified to show high affinity and selectivity for 5-HT2C receptor. Among them, 1H-indole-3-carboxylic acid[6-(2-chloro-pyridin-3-yloxy)-pyridin-3-yl]-amide (15k) exhibits the highest affinity (IC50 = 0.5 nM) with an excellent selectivity (>2000 times) over other serotonin (5-HT1A, 5-HT2A, and 5-HT6) and dopamine (D2-D4) receptors.
- Park, Chul Min,Kim, So Young,Park, Woo Kyu,Park, No Sang,Seong, Churl Min
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supporting information; experimental part
p. 3844 - 3847
(2009/04/16)
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- Design, synthesis, and biological activity of potent and selective inhibitors of mast cell tryptase
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A new series of novel mast cell tryptase inhibitors is reported, which features the use of an indole structure as the hydrophobic substituent on a m-benzylaminepiperidine template. The best members of this series display good in vitro activity and excellent selectivity against other serine proteases.
- Hopkins, Corey R.,Czekaj, Mark,Kaye, Steven S.,Gao, Zhongli,Pribish, James,Pauls, Henry,Liang, Guyan,Sides, Keith,Cramer, Dona,Cairns, Jennifer,Luo, Yongyi,Lim, Heng-Keang,Vaz, Roy,Rebello, Sam,Maignan, Sebastian,Dupuy, Alain,Mathieu, Magali,Levell, Julian
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p. 2734 - 2737
(2007/10/03)
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