Abstract
Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.
MeSH terms
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Animals
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Models, Molecular
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Molecular Structure
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Indoles
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Intracellular Signaling Peptides and Proteins
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indole
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases