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

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 21; pp. 5127 - 5133
• Main Authors: Alonso, Juan Antonio, Andrés, Miriam, Bravo, Mónica, Buil, Maria Antonia, Calbet, Marta, Castro, Jordi, Eastwood, Paul R., Esteve, Cristina, Ferrer, Manel, Forns, Pilar, Gómez, Elena, González, Jacob, Lozoya, Estrella, Mir, Marta, Moreno, Imma, Petit, Silvia, Roberts, Richard S., Sevilla, Sara, Vidal, Bernat, Vidal, Laura, Vilaseca, Pere
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2014
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Acetates - pharmacokinetics; Bridged Bicyclo Compounds - chemistry; CRTh2 antagonist; Half-Life; Humans; Hydrogen bond acceptor; Hydrogen Bonding; Long residence time; Models, Chemical; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - metabolism; Structure-Activity Relationship; Structure–activity relationship (SAR); Structure–kinetic relationship (SKR); Structure–activity relationship (SAR); Structure–kinetic relationship (SKR); Long residence time; CRTh2 antagonist; Hydrogen bond acceptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.08.028

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 ⩾24h.