期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 2, 期 8, 页码 644-649出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml2001196
关键词
CRTH2 receptor; prostaglandin D2; antagonist; indolinone; asthma; atopic dermatitis
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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