- SUBSTITUTED HETEROCYCLIC AMIDE COMPOUND AND PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USE THEREOF
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Provided are a substituted heterocyclic amide compound having a selective inhibitory effect on RIPK1, and a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, and a pharmaceutical composition containing the compound, and the
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Paragraph 0175-0176; 0247-0248
(2022/02/02)
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- Iron-Catalyzed Radical Activation Mechanism for Denitrogenative Rearrangement Over C(sp3)–H Amination
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An iron-catalyzed denitrogenative rearrangement of 1,2,3,4-tetrazole is developed over the competitive C(sp3)–H amination. This catalytic rearrangement reaction follows an unprecedented metalloradical activation mechanism. Employing the developed method, a wide number of complex-N-heterocyclic product classes have been accessed. The synthetic utility of this radical activation method is showcased with the short synthesis of a bioactive molecule. Collectively, this discovery underlines the progress of radical activation strategy that should find wide application in the perspective of medicinal chemistry, drug discovery and natural product synthesis research.
- Roy, Satyajit,Das, Sandip Kumar,Khatua, Hillol,Das, Subrata,Singh, Krishna Nand,Chattopadhyay, Buddhadeb
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supporting information
p. 8772 - 8780
(2021/03/16)
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- Iron-Catalyzed Amination of Strong Aliphatic C(sp3)-H Bonds
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A concept for intramolecular denitrogenative C(sp3)-H amination of 1,2,3,4-tetrazoles bearing unactivated primary, secondary, and tertiary C-H bonds is discovered. This catalytic amination follows an unprecedented metalloradical activation mechanism. The utility of the method is showcased with the short synthesis of a bioactive molecule. Moreover, an initial effort has been embarked on for the enantioselective C(sp3)-H amination through the catalyst design. Collectively, this study underlines the development of C(sp3)-H bond functionalization chemistry that should find wide application in the context of drug discovery and natural product synthesis.
- Das, Sandip Kumar,Roy, Satyajit,Khatua, Hillol,Chattopadhyay, Buddhadeb
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supporting information
p. 16211 - 16217
(2020/10/26)
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- Design and structural analysis of aromatic inhibitors of type II dehydroquinase from mycobacterium tuberculosis
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3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors. A range of carbon-carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high-micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3-nitrobenzylgallate- and 5-aminoiso-phthalate-based analogues.
- Howard, Nigel I.,Dias, Marcio V.B.,Peyrot, Fabienne,Chen, Liuhong,Schmidt, Marco F.,Blundell, Tom L.,Abell, Chris
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p. 116 - 133
(2015/04/14)
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- 6-alkoxy-5-aryl-3-pyridinecarboxamides, a new series of bioavailable cannabinoid receptor type 1 (CB1) antagonists including peripherally selective compounds
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We identified 6-alkoxy-5-aryl-3-pyridinecarboxamides as potent CB1 receptor antagonists with high selectivity over CB2 receptors. The series was optimized to reduce lipophilicity compared to rimonabant to achieve peripherally active molecules with minimal central effects. Several compounds that showed high plasma exposures in rats were evaluated in vivo to probe the contribution of central vs peripheral CB1 agonism to metabolic improvement. Both rimonabant and 14g, a potent brain penetrant CB1 receptor antagonist, significantly reduced the rate of body weight gain. However, 14h, a molecule with markedly reduced brain exposure, had no significant effect on body weight. PK studies confirmed similarly high exposure of both 14h and 14g in the periphery but 10-fold lower exposure in the brain for 14h. On the basis of these data, which are consistent with reported effects in tissue-specific CB1 receptor KO mice, we conclude that the metabolic benefits of CB1 receptor antagonists are primarily centrally mediated as originally believed.
- R?ver, Stephan,Andjelkovic, Mirjana,Bénardeau, Agnès,Chaput, Evelyne,Guba, Wolfgang,Hebeisen, Paul,Mohr, Susanne,Nettekoven, Matthias,Obst, Ulrike,Richter, Wolfgang F.,Ullmer, Christoph,Waldmeier, Pius,Wright, Matthew B.
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p. 9874 - 9896
(2014/01/17)
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- 3-Pyridinecarboxamide derivatives as HDL-cholesterol raising agents
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The present invention relates to a method of raising HDL cholesterol comprising administering to a patient in need thereof a compound of the formula wherein A, G, R1 to R8 and R17 are as defined in the description.
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Page/Page column 16
(2008/06/13)
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- SIX-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS
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The present invention provides compounds of Formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, R3 and R11 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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- Synthesis and structure-activity relationships of pyrazine-pyridine biheteroaryls as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors
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There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Palladium-catalyzed C-C bond, C-N bond formation reactions were used to assemble various pyrazine-pyridine biheteroaryls as potent VEGFR-2 inhibitors. Among them, 4-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-ylamino}-butan-1-ol (39) and N-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-yl}-N′, N′-dimethyl-ethane-1,2-diamine (41) exhibited the highest kinase selectivity against fibroblast growth factor receptor kinase, platelet-derived growth factor receptor kinase, and glycogen synthase kinase-3. All of these compounds showed good cellular potency to inhibit VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC) but with modest effects on the unstimulated growth of HUVEC. The low inhibition of these compounds to the growth of tumor cell lines, such as HeLa, HCT-116, and A375 further confirms that these VEGFR-2 inhibitors are not cytotoxic agents. The in vivo antitumor activity of 39 and 41 were demonstrated in the A375 human melanoma xenograft nude mice model. Molecular modeling (QSAR analysis) was conducted in an attempt to rationalize the observed structure-activity relationship.
- Kuo, Gee-Hong,Prouty, Catherine,Wang, Aihua,Emanuel, Stuart,DeAngelis, Alan,Zhang, Yan,Song, Fengbin,Beall, Lawrence,Connolly, Peter J.,Karnachi, Prahba,Chen, Xin,Gruninger, Robert H.,Sechler, Jan,Fuentes-Pesquera, Angel,Middleton, Steven A.,Jolliffe, Linda,Murray, William V.
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p. 4892 - 4909
(2007/10/03)
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- Herbicidal pyridine compounds
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Herbicidal 3- and/or 5-halogenomethyl-pyrid-2-yloxyphenoxy compounds and processes for making and using the same. Intermediates for making these compounds and their preparation are also disclosed. Thus, for example, 2-chloro-5-trichloromethylpyridine is prepared by a liquid phase chlorination of 3-methylpyridine under the influence of ultra violet light.
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