- BIFUNCTIONAL COMPOUNDS
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The invention provides a bifunctional compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said Targeting Ligand, Linker and Degron are as described herein.
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Page/Page column 51; 85; 86
(2021/05/07)
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- IMMUNOPROTEASOME INHIBITORS
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Provided herein are compounds, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that are immunoproteasome (such as LMP2 and LMP7) inhibitors. The compounds described herein can be useful for the treatment of diseases treatable by inhibition of immunoproteasomes. Also provided herein are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Paragraph 0237; 0405
(2019/06/09)
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- A Series of Enthalpically Optimized Docetaxel Analogues Exhibiting Enhanced Antitumor Activity and Water Solubility
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A dual-purpose strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of C-2- and C-3′-modified analogues. Both aims were realized when the C-3′ phenyl group present in docetaxel was replaced with a propargyl alcohol. The resulting compound, 3f, was able to overcome drug resistance in cultured P-gp-overexpressing tumor cells and showed greater activity than docetaxel against drug-resistant A2780/AD ovarian cancer xenografts in mice. In addition, the considerably lower hydrophobicity of 3f relative to both docetaxel and paclitaxel led to better aqueous solubility. A molecular model of tubulin-bound 3f revealed novel hydrogen-bonding interactions between the propargyl alcohol and the polar environment provided by the side chains of Ser236, Glu27, and Arg320.
- Ma, Yun-Tao,Yang, Yanting,Cai, Pei,Sun, De-Yang,Sánchez-Murcia, Pedro A.,Zhang, Xiao-Ying,Jia, Wen-Qiang,Lei, Lei,Guo, Mengqi,Gago, Federico,Wang, Hongbo,Fang, Wei-Shuo
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supporting information
p. 524 - 533
(2018/03/30)
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- Structure-based design of potent small-molecule binders to the S-component of the ECF transporter for thiamine
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Energy-coupling factor (ECF) transporters are membrane-protein complexes that mediate vitamin uptake in prokaryotes. They bind the substrate through the action of a specific integral membrane subunit (S-component) and power transport by hydrolysis of ATP
- Swier, Lotteke J.Y.M.,Monjas, Leticia,Guskov, Albert,De Voogd, Alrik R.,Erkens, Guus B.,Slotboom, Dirk J.,Hirsch, Anna K. H.
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p. 819 - 826
(2015/03/30)
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- From libraries to candidate: The discovery of new ultra long-acting dibasic β2-adrenoceptor agonists
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Libraries of dibasic compounds designed around the molecular scaffold of the DA2/β2 dual agonist sibenadet (Viozan) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β2-agonist with high selectivity and a duration of action commensurable with once daily dosing.
- Alcaraz, Lilian,Bailey, Andrew,Cadogan, Elaine,Connolly, Stephen,Jewell, Robert,Jordan, Stephen,Kindon, Nicholas,Lister, Andrew,Lawson, Mandy,Mullen, Alexander,Dainty, Ian,Nicholls, David,Paine, Stuart,Pairaudeau, Garry,Stocks, Michael J.,Thorne, Phillip,Young, Alan
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p. 689 - 695
(2012/03/26)
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- Cycloalkyl-dione Derivatives And Methods Of Their Use
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The present invention is directed to compounds of formula I: wherein A is n is 0, 1, or 2; m is 0 or 1; R1 is H or C1-6alkyl and R2 is H, C1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubsti
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Page/Page column 17
(2013/02/28)
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- Cyclopentane-1,3-dione: A novel isostere for the carboxylic acid functional group. Application to the design of potent thromboxane (A2) receptor antagonists
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Cyclopentane-1,3-diones are known to exhibit pKa values typically in the range of carboxylic acids. To explore the potential of the cyclopentane-1,3-dione unit as a carboxylic acid isostere, the physical-chemical properties of representative co
- Ballatore, Carlo,Soper, James H.,Piscitelli, Francesco,James, Michael,Huang, Longchuan,Atasoylu, Onur,Huryn, Donna M.,Trojanowski, John Q.,Lee, Virginia M.-Y.,Brunden, Kurt R.,Smith, Amos B.
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experimental part
p. 6969 - 6983
(2011/12/02)
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- Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate.
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3-Deazathiamin diphosphate (deazaTPP) and a second thiamin diphosphate (TPP) analogue having a benzene ring in place of the thiazolium ring have been synthesised. These compounds are both extremely potent inhibitors of pyruvate decarboxylase from Zymomonas mobilis; binding is competitive with TPP and is essentially irreversible even though no covalent linkage is formed. DeazaTPP binds approximately seven-fold faster than TPP and at least 25,000-fold more tightly (K(i) less than 14 pM). DeazaTPP is also a potent inhibitor of the E1 subunit of alpha-ketoglutarate dehydrogenase from E. coli and binds more than 70-fold faster than TPP. In this case slow reversal of the inhibition could be observed and a K(i) value of about 5 nM was calculated (ca. 500-fold tighter binding than TPP).
- Mann, Stephane,Perez Melero, Concepcion,Hawksley, Dan,Leeper, Finian J
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p. 1732 - 1741
(2007/10/03)
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