- Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment
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Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.
- Chen, Qiang,Gou, Kun,Li, Chungen,Liu, Huan,Liu, Xiaocong,Luo, Youfu,Luo, Yuan,Tao, Lei,Yang, Xiaowei,Yang, Xinyu,Zeng, Ting,Zhao, Yinglan,Zhong, Xi,Zhou, Xia,Zhou, Yue
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p. 18175 - 18192
(2021/12/27)
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- Mechanistic Evaluation of Bioorthogonal Decaging with trans-Cyclooctene: The Effect of Fluorine Substituents on Aryl Azide Reactivity and Decaging from the 1,2,3-Triazoline
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Bioorthogonal prodrug activation/decaging strategies need to be selective, rapid and release the drug from the masking group upon activation. The rates of the 1,3-dipolar cycloaddition between a trans-cyclooctene (TCO) and a series of fluorine-substituted
- Matikonda, Siddharth S.,Fairhall, Jessica M.,Fiedler, Franziska,Sanhajariya, Suchaya,Tucker, Robert A. J.,Hook, Sarah,Garden, Anna L.,Gamble, Allan B.
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p. 324 - 334
(2018/02/28)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
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Page/Page column 45
(2016/11/07)
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- ALKYNE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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Provided are compounds of formula (Ia) and pharmaceutically acceptable salts thereof, wherein A, B, R 1, R 2, m and n are as defined herein, which are active as inhibitors of S-Nitrosoglutathione reductase (GSNOR). These compounds prevent, inhibit, or suppress the action of GSNOR and are therefore useful in the treatment of GSNOR mediated diseases, disorders, syndromes or conditions such as, e.g., pulmonary hypertension, acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis, interstitial lung diseases, cystic fibrosis and chronic obstructive pulmonary disease (COPD).
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Page/Page column 74; 80
(2016/05/02)
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- PYRAZOLE DERIVATIVES AS 5-LO INHIBITORS
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The invention relates to compounds of formula (I) processes for their preparation, their use as 5-lipoxygenase inhibitors and pharmaceutical compositions containing the same.
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Page/Page column 90
(2009/07/03)
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- 4-cyano-2,5-difluoroaniline preparation process
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PCT No. PCT/EP96/03642 Sec. 371 Date Feb. 20, 1998 Sec. 102(e) Date Feb. 20, 1998 PCT Filed Aug. 19, 1996 PCT Pub. No. WO97/08136 PCT Pub. Date Mar. 6, 1997The present invention relates to a process for preparing 4-cyano-2,5-difluoroaniline, which is an i
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- Synthesis of [1]Benzothieno[3,2-d]pyrimidines Substituted with Electron Donating Substituents on the Benzene Ring
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Various 2-fluorobenzonitriles were converted to the corresponding 3-amino[1]benzothiophenecarboxylic acid esters, which in turn were annulated with formamidine or various equivalents to produce the desired tricyclic benzothienopyrimidines. Various methoxy and nitro/amino substituants were placed on the phenyl ring, requiring several different strategies to prepare the desired benzothiophenes. Several different pyrimidone annulations were also required. The use of an electron rich 2-bromobenzonitrile in a four-step one-pot low temperature lithiation sequence to produce highly electron-rich amino[1]benzothiophenecarboxylate esters is also described. The synthesis of 7-amino-8-fluoro[1]benzothieno[3,2-d]pyrimid-4(3H)-one was relatively straightforward, but synthesis of the corresponding 7-amino-8-protio analogue proved to be very difficult, and required several approaches before a successful one was found.
- Bridges, Alexander J.,Zhou, Hairong
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p. 1163 - 1172
(2007/10/03)
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- Anthranilonitrile derivatives as useful agents for promoting growth, improving feed efficiency, and for increasing the lean meat to fat ratio of warm-blooded animals
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There are provided novel anthranilonitrile derivatives and related compounds which are useful for promoting growth, improving feed efficiency and for increasing the lean meat to fat ratio of warm-blooded animals.
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