title: Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization.
abstract: Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Alonso
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Andrés
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bravo
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Calbet
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: paul.eastwood@almirall.com.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Eastwood
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Peter
authors.initials: P
authors.lastname: Eichhorn
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteve
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Gómez
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Jacob
authors.initials: J
authors.lastname: González
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Mir
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Imma
authors.initials: I
authors.lastname: Moreno
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Petit
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Roberts
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Sevilla
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Vidal
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Vilaseca
authors.affiliation: Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Zanuy
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007275:Injections, Intravenous; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D001643:Bridged Bicyclo Compounds; D007211:Indoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C030374:indole; C036293:prostaglandin D2 receptor
keywords: CRTh2 antagonist; Receptor residence time; Structure–activity relationship (SAR); Structure–kinetic relationship (SKR)