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

Citations Over TimeTop 11% of 2011 papers

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.

Related Papers

• → Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes(2015)37 cited
• → Covalent Coupling of Palmitate to Ovalbumin Inhibits and Blocks the Induction of Oral Tolerance*(2002)10 cited
• Absorption and excretion of 3H-raubasine in human subjects and dogs.(1977)
• → ELECTROLYTE, WATER, AND MERCURY EXCRETION AFTER ORAL ADMINISTRATION OF NEOHYDRIN(1953)8 cited