Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 2, Issue 8, Pages 644-649Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml2001196
Keywords
CRTH2 receptor; prostaglandin D2; antagonist; indolinone; asthma; atopic dermatitis
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New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC(50) = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%). This compound is also active in a mouse model of ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.
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