Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents.
ABSTRACT Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.
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ABSTRACT: Key points Activated NK cells loose CD16 (FcRγIII) and CD62L through a metalloprotease called ADAM17Inhibition of ADAM17 enhances CD16 mediated NK cell function by preserving CD16 on the NK cell surface to enhance ADCC.Blood 03/2013; · 9.78 Impact Factor
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ABSTRACT: This compendium focuses on functionalised sugar amino acids (SAAs) and their 3- to 6-membered nitrogen heterocyclic and carbocyclic analogues. The main benefit of using SAAs and their related nitrogen and carbon congeners in the production of peptidomimetics and glycomimetics is that their properties can be readily altered via modification of their ring size, chemical manipulation of their numerous functional groups and fine-tuning of the stereochemical arrangement of their ring substituents. These building blocks provide access to hydrophilic and hydrophobic peptide isosteres whose physical properties allow entry to a region of chemotherapeutic space which is still under-explored by medicinal chemists. These building blocks are also important in providing amino acids whose inherent conformational bias leads to predisposition to secondary structure upon oligomerisation in relatively short sequences. These foldamers, particularly those containing ω-amino acids, provide an additional opportunity to expand access to the control of structures by artificial peptides. The synthesis and biological evaluation of these building blocks in glycomimetics and peptidomimetics systems keep expanding the reach of the glycosciences to the medical sciences, provide a greater outlook onto the wide range of cellular functions of saccharides and their derivatives involved and greater insight into the nature of oligosaccharide and protein folding.Amino Acids 08/2013; · 3.91 Impact Factor
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ABSTRACT: The tumour necrosis factor-α converting enzyme inhibition activity of a series comprising of novel tartrate-based analogues has been quantitatively analysed in terms of molecular descriptors. The statistically validated quantitative structure-activity relationship models provided rationales to explain the inhibition activity of these congeners. The descriptors identified through combinatorial protocol in multiple linear regression analysis have highlighted the role of Moran autocorrelation of lag 7, weighted by atomic van der Waals volume, presence of both prime and nonprime amide carbonyl oxygen in the tartrate moiety and occurrence of five membered ring bearing substituents at varying sites. A few potential novel tartrate-based analogues have been suggested for further investigation.Indian Journal of Pharmaceutical Sciences 01/2013; 75(1):36-44. · 0.34 Impact Factor