title: Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.
abstract: New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg).
authors.affiliation: Merck Serono S.A., 9 Chemin des Mines, CH-1202 Geneva, Switzerland. stefano.crosignani@merckserono.net
authors.forename: Stefano
authors.initials: S
authors.lastname: Crosignani
authors.forename: Adeline
authors.initials: A
authors.lastname: Prêtre
authors.forename: Catherine
authors.initials: C
authors.lastname: Jorand-Lebrun
authors.forename: Gaële
authors.initials: G
authors.lastname: Fraboulet
authors.forename: Jeyaprakashnarayanan
authors.initials: J
authors.lastname: Seenisamy
authors.forename: John Kallikat
authors.initials: JK
authors.lastname: Augustine
authors.forename: Marc
authors.initials: M
authors.lastname: Missotten
authors.forename: Yves
authors.initials: Y
authors.lastname: Humbert
authors.forename: Christophe
authors.initials: C
authors.lastname: Cleva
authors.forename: Nada
authors.initials: N
authors.lastname: Abla
authors.forename: Hamina
authors.initials: H
authors.lastname: Daff
authors.forename: Olivier
authors.initials: O
authors.lastname: Schott
authors.forename: Manfred
authors.initials: M
authors.lastname: Schneider
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burgat-Charvillon
authors.forename: Delphine
authors.initials: D
authors.lastname: Rivron
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hamernig
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arrighi
authors.forename: Marilène
authors.initials: M
authors.lastname: Gaudet
authors.forename: Simone C
authors.initials: SC
authors.lastname: Zimmerli
authors.forename: Pierre
authors.initials: P
authors.lastname: Juillard
authors.forename: Zoe
authors.initials: Z
authors.lastname: Johnson
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000480:Alkynes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D048430:Cell Shape; D002634:Chemotaxis, Leukocyte; D003877:Dermatitis, Contact / Q000188:drug therapy; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D010642:Phenoxyacetates; D011485:Protein Binding; D011657:Pulmonary Eosinophilia / Q000188:drug therapy / Q000276:immunology; D011869:Radioligand Assay; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C568958:(4-chloro-2-((2-fluoro-5-(propylsulfonyl)phenyl)ethynyl)phenoxy)acetic acid; C568957:(4-chloro-2-((2-methyl-5-(propylsulfonyl)phenyl)ethynyl)phenoxy)acetic acid; D000085:Acetates; D000480:Alkynes; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D010642:Phenoxyacetates; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013450:Sulfones; D010047:Ovalbumin; C036293:prostaglandin D2 receptor