title: Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids.
abstract: Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (K i < 10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C19 > 1 μM). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development.
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: Gordon
authors.initials: G
authors.lastname: Campbell
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Adeline
authors.initials: A
authors.lastname: Prêtre
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Tania
authors.initials: T
authors.lastname: Grippi-Vallotton
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Quattropani
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Bouscary-Desforges
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bombrun
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: Christèle
authors.initials: C
authors.lastname: Frémaux
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Mikaël
authors.initials: M
authors.lastname: Pâquet
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Kamel
authors.initials: K
authors.lastname: El Harkani
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bradshaw
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: Nada
authors.initials: N
authors.lastname: Abla
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Hamina
authors.initials: H
authors.lastname: Daff
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schott
authors.affiliation: Merck Serono S.A. , 9 chemin des Mines, CH-1202 Geneva, Switzerland.
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Pittet
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: Zoë
authors.initials: Z
authors.lastname: Johnson
keywords: CRTH2 (DP2) receptor; antagonists; asthma; tetrazoles