Abstract
Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Dogs
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacokinetics*
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Indoles / pharmacology
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Luteinizing Hormone / metabolism
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Macaca mulatta
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Models, Animal
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Rats
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Receptors, LHRH / antagonists & inhibitors*
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Structure-Activity Relationship
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Tryptamines / chemical synthesis
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Tryptamines / chemistry
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Tryptamines / pharmacokinetics*
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Tryptamines / pharmacology
Substances
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Indoles
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Receptors, LHRH
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Tryptamines
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Luteinizing Hormone