title: Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.
abstract: A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.
authors.affiliation: Merck Serono International S.A., 9 chemin des Mines, Geneva, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Crosignani
authors.forename: Patrick
authors.initials: P
authors.lastname: Page
authors.forename: Marc
authors.initials: M
authors.lastname: Missotten
authors.forename: Véronique
authors.initials: V
authors.lastname: Colovray
authors.forename: Christophe
authors.initials: C
authors.lastname: Cleva
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arrighi
authors.forename: John
authors.initials: J
authors.lastname: Atherall
authors.forename: Jackie
authors.initials: J
authors.lastname: Macritchie
authors.forename: Thierry
authors.initials: T
authors.lastname: Martin
authors.forename: Yves
authors.initials: Y
authors.lastname: Humbert
authors.forename: Marilène
authors.initials: M
authors.lastname: Gaudet
authors.forename: Doris
authors.initials: D
authors.lastname: Pupowicz
authors.forename: Maurizio
authors.initials: M
authors.lastname: Maio
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Pittet
authors.forename: Lucia
authors.initials: L
authors.lastname: Golzio
authors.forename: Claudio
authors.initials: C
authors.lastname: Giachetti
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rocha
authors.forename: Gérald
authors.initials: G
authors.lastname: Bernardinelli
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Filinchuk
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheer
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: André
authors.initials: A
authors.lastname: Chollet
mesh_terms: D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D007211:Indoles / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013141:Spiro Compounds; C036293:prostaglandin D2 receptor