- Pyridine - 2 - amide compound and its preparation method, its pharmaceutical composition and use thereof
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The invention relates to a pyridine-2-amide compound shown as a general formula I as well as a preparation method, a pharmaceutical composition and use thereof. The compound as an integrase inhibitor is used for preparing medicines for treating diseases mediated by various vetrovirus integrases including HIV-1 (Human Immunodeficiency Virus-1) integrase.
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Paragraph 0092; 0097; 0098
(2018/04/01)
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- Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction
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Currently, three HIV-1 integrase (IN) active site-directed inhibitors are in clinical use for the treatment of HIV infection. However, emergence of drug resistance mutations have limited the promise of a long-term cure. As an alternative, allosteric inhibition of IN activity has drawn great attention and several of such inhibitors are under early stage clinical development. Specifically, inhibitors of IN and the cellular cofactor LEDGF/p75 remarkably diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Distinct from the extensively studied 2-(quinolin-3-yl) acetic acid or 1H-indol-3-yl-2-hydroxy-4-oxobut-2-enoic acid chemotypes, this study discloses a new class of selective IN-LEDGF/p75 inhibitors without the carboxylic acid functionality. More significantly, 3-hydroxypicolinamides also show low micromolar inhibition against IN dimerization, providing novel dual IN inhibitors with in vitro therapeutically selective antiviral effect for further development. Finally, our shape-based ROCS pharmacophore model of the 3-hydroxypicolinamide class of compounds provides a new insight into the binding mode of these novel IN-LEDGF/p75 inhibitors.
- Zhang, Feng-Hua,Debnath, Bikash,Xu, Zhong-Liang,Yang, Liu-Meng,Song, Li-Rui,Zheng, Yong-Tang,Neamati, Nouri,Long, Ya-Qiu
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p. 1051 - 1063
(2016/11/09)
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- Inhibitors of type I MetAPs containing pyridine-2-carboxylic acid thiazol-2-ylamide. Part 1: SAR studies on the determination of the key scaffold
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Systematic SAR studies on the HTS hit pyridine-2-carboxylic acid thiazol-2-ylamide (PACT) analogues revealed that the scaffold of PCAT is indispensable for the inhibition of type I MetAP. For effective inhibition of the enzyme, the most suitable position to modify is the 3-position of the pyridine ring of PCAT, and the best substituents are those containing O or N atoms connected directly with the pyridine ring. These findings provide useful information for the design and discovery of more potent inhibitors of type I MetAPs.
- Luo, Qun-Li,Li, Jing-Ya,Liu, Zhi-Ying,Chen, Ling-Ling,Li, Jia,Ye, Qi-Zhuang,Nan, Fa-Jun
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p. 635 - 638
(2007/10/03)
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