title: Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists.
abstract: Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.
authors.affiliation: Drug Discovery Division, 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: Drug Discovery Division, Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Buil
authors.affiliation: Drug Discovery Division, 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-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Casado
authors.affiliation: Drug Discovery Division, Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Castro
authors.affiliation: Drug Discovery Division, Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Eastwood
authors.affiliation: Drug Discovery Division, 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: Drug Discovery Division, 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-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Forns
authors.affiliation: Drug Discovery Division, 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: Drug Discovery Division, 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: Drug Discovery Division, Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: rick.roberts@almirall.com.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Roberts
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D010880:Piperidines / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D010880:Piperidines; D011720:Pyrazoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C031280:pyrazole; C036293:prostaglandin D2 receptor
keywords: CRTh2 antagonist; Permeability; Prodrug; Receptor residence time; Structure–activity relationship (SAR); Structure–kinetic relationship (SKR)