Abstract
During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC20 of 3.0 μM and EC50 of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.
MeSH terms
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Administration, Oral
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Biological Availability
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Cell Line
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Drug Discovery*
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Humans
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Hypoparathyroidism / drug therapy*
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Methylurea Compounds / administration & dosage
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Methylurea Compounds / pharmacology
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Methylurea Compounds / therapeutic use*
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Receptor, Parathyroid Hormone, Type 1 / agonists*
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / pharmacokinetics*
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Small Molecule Libraries / pharmacology*
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Small Molecule Libraries / therapeutic use
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Sulfones / administration & dosage
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Sulfones / pharmacology
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Sulfones / therapeutic use*
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Urea / administration & dosage
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Urea / pharmacokinetics*
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Urea / pharmacology*
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Urea / therapeutic use
Substances
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CH5447240
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Methylurea Compounds
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PTH1R protein, human
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Receptor, Parathyroid Hormone, Type 1
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Small Molecule Libraries
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Sulfones
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Urea