Abstract
The lead optimization of a novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo[a]carbazole lead 2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to 2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50 nM. Analog 21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag.
MeSH terms
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Benzene Derivatives / chemical synthesis*
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Benzene Derivatives / chemistry
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Benzene Derivatives / pharmacology*
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Carbazoles / chemical synthesis*
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Carbazoles / chemistry
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Carbazoles / pharmacology*
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Combinatorial Chemistry Techniques
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Drug Design
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Humans
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Inhibitory Concentration 50
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Megakaryocytes / metabolism
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Molecular Structure
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Nuclear Magnetic Resonance, Biomolecular
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Receptors, Thrombopoietin / agonists*
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Receptors, Thrombopoietin / chemistry
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Structure-Activity Relationship
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Thrombopoietin* / chemistry
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Thrombopoietin* / metabolism
Substances
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Benzene Derivatives
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Carbazoles
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Receptors, Thrombopoietin
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Thrombopoietin