- Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73
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CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5′-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.
- Beatty, Joel W.,Lindsey, Erick A.,Thomas-Tran, Rhiannon,Debien, Laurent,Mandal, Debashis,Jeffrey, Jenna L.,Tran, Anh T.,Fournier, Jeremy,Jacob, Steven D.,Yan, Xuelei,Drew, Samuel L.,Ginn, Elaine,Chen, Ada,Pham, Amber T.,Zhao, Sharon,Jin, Lixia,Young, Stephen W.,Walker, Nigel P.,Leleti, Manmohan Reddy,Moschütz, Susanne,Str?ter, Norbert,Powers, Jay P.,Lawson, Kenneth V.
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p. 3935 - 3955
(2020/05/27)
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- Metal free [4+1] and [5+1] annulation reactions to prepare heterocycles using DMF and its derivatives as one-carbon source
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1,2,4-Triazolo[3,4-a]pyridines and related heterocycles and substituted triazines were commonly discovered scaffolds in a variety of pharmaceutical and agrochemical agents. Herein, we report a highly efficient and practical method using DMF and its derivative for the [4+1] and [5+1] annulation reactions to prepare these heterocycles. This metal free reaction takes advantages of shelf stable DMF as solvent and carbon donor, imidazole chloride as a catalyst, the mild reaction condition tolerates a broad substrate range and substitutes. The prepared 3-unsubstituted 1,2,4-triazolo[3,4-a]pyridine and derivatives allow further introduction of a variety of functional group1 at 3-position.
- Liu, Lingfeng,Qiao, Chunhua,Shen, Bei,Xu, Yiwen
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- FUSED RING DERIVATIVE AS A2A RECEPTOR INHIBITOR
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Disclosed are a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and an application of the compound or slat in preparation of drugs for treating diseases related to an A2A receptor.
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Paragraph 0100-0104
(2020/08/09)
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- Copper(i)-catalyzed benzylation of triazolopyridine through direct C-H functionalization
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A general and efficient copper-catalyzed benzylation reaction of triazolopyridine with N-tosylhydrazones was developed. This reaction forms a C(sp2)-C(sp3) bond through cross-coupling, and represents an exceedingly practical method t
- Reddy Lonka, Madhava,Zhang, Jinquan,Gogula, Thirupathi,Zou, Hongbin
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p. 7455 - 7460
(2019/08/20)
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- HETEROAROMATIC COMPOUNDS AS PI3 KINASE MODULATORS AND METHODS OF USE
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The present invention provides heteroaromatic derivatives and pharmaceutical acceptable salts and formulations thereof useful in modulating the protein kinase activity, especially phosphatidylinositol 3-kinases (PI3 kinases) and mTOR, and in modulating inter- and/or intra-cellular signaling activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0451
(2014/05/20)
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