Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy.
The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day. Herein we described the pharmacological profile of LAS191859, a novel, potent and selective CRTh2 antagonist. In vitro evidence in GTPγS binding studies indicate that LAS191859 is a CRTh2 antagonist with activity in the low nanomolar range. This potency is also maintained in cellular assays performed with human eosinophils and whole blood. The main differentiation of LAS191859 vs other CRTh2 antagonists is in its receptor binding kinetics. LAS191859 has a residence time half-life of 21h at CRTh2 that translates into a long-lasting in vivo efficacy that is independent of plasma levels. We believe that the strategy behind this compound will allow optimal efficacy and posology for chronic asthma treatment.
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: marta.calbet@almirall.com.
Marta
M
Calbet
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Miriam
M
Andrés
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Clara
C
Armengol
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Mónica
M
Bravo
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Peter
P
Eichhorn
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Rosa
R
López
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Vicente
V
García-González
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Richard
R
Roberts
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Montserrat
M
Miralpeix
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D048430:Cell Shape / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006207:Half-Life; D007700:Kinetics; D008297:Male; D051379:Mice; D011448:Prostaglandin Antagonists / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D014162:Transfection
D018927:Anti-Asthmatic Agents; C000625667:LAS191859; D011448:Prostaglandin Antagonists; D011725:Pyridines; D011758:Pyrroles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C036293:prostaglandin D2 receptor
Asthma; Blood eosinophilia; CRTh2 receptor; Long duration of action; Long receptor residence time