- Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist
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Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. RORγt is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel RORγt inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.
- Chen, Lei,Su, Mei,Jin, Qiu,Wang, Wei,Wang, Chun-Gu,Assani, Israa,Wang, Mu-Xuan,Zhao, Shi-Feng,Lv, Shen-Min,Wang, Jia-Wei,Sun, Bo,Li, Yan,Liao, Zhi-Xin
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p. 16106 - 16131
(2021/11/18)
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- One-Pot Synthesis of Functionalized Carbazoles via a CAN-Catalyzed Multicomponent Process Comprising a C-H Activation Step
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The microwave-promoted three-component reaction between o-nitrochalcones, primary amines and β-dicarbonyl compounds in the presence of Ce(IV) ammonium nitrate constitutes the first example of a multicomponent carbazole synthesis. This reaction furnishes highly substituted and functionalized carbazole derivatives via a double annulation process that generates two C-C and two C-N bonds, with water as the only side product. Mechanistically, this transformation has some unusual features that include an intramolecular coupled hydrogenation-dehydrogenation process, the functionalization of a C-H group by direct attack onto a nitrogen function and a CAN-catalyzed reduction via hydride transfer from ethanol. The mechanisms of these reactions were studied with the aid of computational techniques.
- González, Juan F.,Rocchi, Damiano,Tejero, Tomás,Merino, Pedro,Menéndez, J. Carlos
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supporting information
p. 7492 - 7502
(2017/07/26)
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- A 1H-indazole derivatives preparation method
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The invention provides a method for preparing 3-methyl-5-R-1H-indazole easily, safely and efficiently without performing any hydrazine hydrate reflux heating reaction or purifying a product and making the product pass through a column. The method at least comprises the following steps of: a, performing a diazo-reaction on 2-amino-5-R-hypnone serving as a raw material or an intermediate under the condition of an acid solution to generate a diazo salt; b, slowly adding a stannous chloride-hydrate hydrochloric acid solution into the diazo salt obtained in the step a for reacting to generate a 3-methyl-5-R-1H-indazole solution; and c, cooling the solution obtained in the step b under the condition that the pH value is 8-9, and precipitating a product out, wherein R in the steps above represents H or a halogen element.
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Paragraph 0027-0029
(2017/02/24)
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- Design and synthesis of a new chromophore, 2-(4-nitrophenyl)benzofuran, for two-photon uncaging using near-IR light
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A new chromophore, 2-(4-nitrophenyl)benzofuran (NPBF), was designed for two-photon (TP) uncaging using near-IR light. The TP absorption (TPA) cross-sections of the newly designed NPBF chromophore were determined to be 18 GM at 720 nm and 54 GM at 740 nm in DMSO. The TP uncaging reaction of a caged benzoate with the NPBF chromophore quantitatively produced benzoic acid with an efficiency (δu) of ~5.0 GM at 740 nm. The TP fragmentation of an EGTA unit was observed with δu = 16 GM. This behavior makes the new chromophore a promising TP photoremovable protecting group for physiological studies.
- Komori, Naomitsu,Jakkampudi, Satish,Motoishi, Ryusei,Abe, Manabu,Kamada, Kenji,Furukawa, Ko,Katan, Claudine,Sawada, Wakako,Takahashi, Noriko,Kasai, Haruo,Xue, Bing,Kobayashi, Takayoshi
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supporting information
p. 331 - 334
(2016/01/09)
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- Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test
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To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50 = 35 nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9- condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.
- Igawa, Hideyuki,Takahashi, Masashi,Ikoma, Minoru,Kaku, Hiromi,Kakegawa, Keiko,Kina, Asato,Aida, Jumpei,Okuda, Shoki,Kawata, Yayoi,Noguchi, Toshihiro,Hotta, Natsu,Yamamoto, Syunsuke,Nakayama, Masaharu,Nagisa, Yasutaka,Kasai, Shizuo,Maekawa, Tsuyoshi
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p. 2504 - 2518
(2016/05/09)
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- Photolabile compound and substrate for oligomer probe array with the same
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Provided is a substrate for an oligomer probe array to which a photolabile material having an acetylene derivative is directly attached or attached via a linker.
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Page/Page column 12
(2009/08/14)
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- Photolabile compound, oligomer probe array and substrate for oligomer probe array containing the same, and manufacturing method of the same
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A photolabile compound, an oligomer probe array, and a susbtrate for oligomer probe array comprising the same, and a manufacturing method of the same are disclosed. wherein, X is or R1 is hydrogen, an alkyl group, or an acetyl group, R2 is hydrogen, methyl, ethyl, propyl, or phenyl.
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Page/Page column 30
(2008/12/07)
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- Photolabile Compound and Substrate for Oligomer Probe Array with the Same
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Provided is a substrate for an oligomer probe array to which a photolabile material having an acetylene derivative is directly attached or attached via a linker.
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- PHOTOLABILE COMPOUND, OLIGOMER PROBE ARRAY AND SUBSTRATE FOR OLIGOMER PROBE ARRAY CONTAINING THE SAME, AND MANUFACTURING METHOD OF THE SAME
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A photolabile compound, an oligomer probe array, and a substrate for oligomer probe array comprising the same, and a manufacturing method of the same are disclosed.
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- Substituent effects on the lifetimes and reactivities of arylnitrenium ions studied by laser flash photolysis and photothermal beam deflection
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Photolysis of 5-substituted-N-tert-butyl-3-methylanthranilium ion produces transient N-tert-butyl-(2-acetyl-4-substituted) phenylnitrenium ions. This is confirmed by identification of the stable products, transient absorption experiments, and photothermal
- Robbins, Rebecca J.,Laman, David M.,Falvey, Daniel E.
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p. 8127 - 8135
(2007/10/03)
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