Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization

  • Bioorg Med Chem Lett. 2014 Nov 1;24(21):5123-6. doi: 10.1016/j.bmcl.2014.08.029.
Juan Antonio Alonso  1 ,  Miriam Andrés  1 ,  Mónica Bravo  1 ,  Marta Calbet  1 ,  Paul R Eastwood  2 ,  Peter Eichhorn  1 ,  Cristina Esteve  1 ,  Manel Ferrer  1 ,  Elena Gómez  1 ,  Jacob González  1 ,  Marta Mir  1 ,  Imma Moreno  1 ,  Silvia Petit  1 ,  Richard S Roberts  1 ,  Sara Sevilla  1 ,  Bernat Vidal  1 ,  Laura Vidal  1 ,  Pere Vilaseca  1 ,  Miriam Zanuy  1
Affiliations
  • 1. Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
  • 2. Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: [email protected].
PMID: 25437505 DOI: 10.1016/j.bmcl.2014.08.029
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.

Keywords
CRTh2 antagonist; Receptor residence time; Structure–activity relationship (SAR); Structure–kinetic relationship (SKR).