Abstract
A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.
Keywords:
carbonic anhydrase activators; heterocycles; histamine-related compounds.
MeSH terms
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Carbonic Anhydrase I / drug effects
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Carbonic Anhydrase I / metabolism*
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Carbonic Anhydrase II / drug effects
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Carbonic Anhydrase II / metabolism
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Carbonic Anhydrase V / drug effects
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Carbonic Anhydrase V / metabolism
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Carbonic Anhydrases / drug effects
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Carbonic Anhydrases / metabolism
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis
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Heterocyclic Compounds, 4 or More Rings / chemistry*
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Histamine / analogs & derivatives
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Histamine / chemical synthesis
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Histamine / chemistry*
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Histamine / pharmacology*
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Humans
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Imidazoles / chemistry
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Protein Isoforms / drug effects
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Protein Isoforms / metabolism
Substances
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Heterocyclic Compounds, 4 or More Rings
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Imidazoles
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Protein Isoforms
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imidazole
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Histamine
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Carbonic Anhydrase I
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Carbonic Anhydrase II
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Carbonic Anhydrase V
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CA13 protein, human
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CA2 protein, human
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Carbonic Anhydrases
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carbonic anhydrase VI