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Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: The role of a hydrogen-bond acceptor in long receptor residence times
Institution:1. Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain;2. Almirall-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain;1. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 avenue de la terrasse, 91198 Gif-sur-Yvette Cedex, France;2. UMR CNRS 8126, Université Paris-Sud, Institut Gustave Roussy, 114 rue Edouard-Vaillant, 94805 Villejuif Cedex, France;1. Institute of Chemistry, St. Petersburg State University, 199034 St. Petersburg, Russian Federation;2. Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russian Federation;1. AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom;2. AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France;1. Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India;2. Green Chemistry & Sustainability Engineering, Department of Chemical Engineering, Institute of Chemical Technology, Matunga, Mumbai 400019, India;3. Tezpur University, Tezpur, India;1. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France;2. Protein Phosphorylation & Human Disease Group, CNRS, USR 3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France;3. Plate-forme ImPACcell, UMS-3480, Université de Rennes 1, Campus de Villejean, 2 avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France;4. Centre de Biophysique Moléculaire, CNRS, UPR 4301, Université d’Orléans et INSERM, rue Charles Sadron, 45071 Orléans Cedex 2, France;5. ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, France
Abstract:The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (Rcore  H) gives access to compounds with dissociation half-lives of ⩾24 h.
Keywords:CRTh2 antagonist  Long residence time  Hydrogen bond acceptor  Structure–activity relationship (SAR)  Structure–kinetic relationship (SKR)
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