- Amide compound and derivative thereof, preparation method, pharmaceutical composition and application thereof
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The invention discloses an amide compound and derivative thereof, a preparation method, a pharmaceutical composition and application thereof. The structure of the amide compound is shown as a formula (I). The derivatives of theamide compound relate to a stereoisomer, a tautomer, a metabolite, a metabolic precursor, a prodrug, a solvate, a salt of the solvate, a crystal, a pharmaceutically acceptable salt or a mixture of the above of theamide compound. The amide compound and the derivative thereof have an efficient inhibition effect on indoleamine 2, 3-dioxygenase 1, and can be used for preparing medicines for treating indoleamine 2, 3-dioxygenase 1 mediated immunosuppression related diseases, the prepared medicine can exert the medicine effect at the molecular level and is wide in application, and the synthesis method of the compound is simple, convenient and easy to operate.
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- Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class i HDAC Enzymes and Cancer Cell Proliferation
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AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g., JT86, IC50 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines, and up to 70-fold less toxicity in normal human cells. JT86 was ninefold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modeling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefits in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.
- Tng, Jiahui,Lim, Junxian,Wu, Kai-Chen,Lucke, Andrew J.,Xu, Weijun,Reid, Robert C.,Fairlie, David P.
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supporting information
p. 5956 - 5971
(2020/06/05)
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- Synthesis and pharmacological evaluation of 1-Alkyl-N-[(1R)-1-(4- fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents
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We synthesized and evaluated inhibitory activity against T-type Ca 2+ channels for a series of 1-alkyl-N- [(1R)-1-(4-fluorophenyl)-2- methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca2+ channel blocker. Oral administration of N- [(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl] piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca2+ channel blockers.
- Watanuki, Susumu,Matsuura, Keisuke,Tomura, Yuichi,Okada, Minoru,Okazaki, Toshio,Ohta, Mitsuaki,Tsukamoto, Shin-Ichi
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p. 1376 - 1385
(2012/01/05)
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