Abstract
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
MeSH terms
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Administration, Oral
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Aniline Compounds / chemical synthesis
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology*
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Animals
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Biological Availability
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Cell Line
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Drug Evaluation, Preclinical
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Humans
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Molecular Structure
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Molecular Weight
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Piperidones / chemical synthesis
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Piperidones / chemistry
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Piperidones / pharmacology*
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Rats
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Receptors, G-Protein-Coupled / antagonists & inhibitors*
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Small Molecule Libraries
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Stereoisomerism
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Structure-Activity Relationship
Substances
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(3,4-dichlorophenyl)methyl(2-oxo-2-(3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl)ethyl)amine
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Aniline Compounds
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Piperidones
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Receptors, G-Protein-Coupled
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Small Molecule Libraries
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UTS2R protein, human