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Optimization of the Central Core of Indolinone-Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists.

ABSTRACT: 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 (IC50 = 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.

SUBMITTER: Crosignani S

PROVIDER: S-EPMC4018112 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Optimization of the Central Core of Indolinone-Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists.

Crosignani Stefano S Jorand-Lebrun Catherine C Page Patrick P Campbell Gordon G Colovray Véronique V Missotten Marc M Humbert Yves Y Cleva Christophe C Arrighi Jean-François JF Gaudet Marilène M Johnson Zoe Z Ferro Pamela P Chollet André A

ACS medicinal chemistry letters 20110609 8

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 (IC50 = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimi ...[more]

PMID: 24900359

Dataset Information

Optimization of the Central Core of Indolinone-Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists.

Publications

Optimization of the Central Core of Indolinone-Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists.

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