title: 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.
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Crosignani
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Jorand-Lebrun
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Page
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Gordon
authors.initials: G
authors.lastname: Campbell
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Véronique
authors.initials: V
authors.lastname: Colovray
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Missotten
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Humbert
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cleva
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arrighi
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Marilène
authors.initials: M
authors.lastname: Gaudet
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Johnson
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ferro
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: André
authors.initials: A
authors.lastname: Chollet
keywords: CRTH2 receptor, prostaglandin D2, antagonist, indolinone, asthma, atopic dermatitis