Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy

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• 作者：Marta Calbet ; ^{marta.calbet@almirall.com" class="auth_mail" title="E-mail the corresponding author} ; Miriam André ; s ; Clara Armengol ; Mó ; nica Bravo ; Peter Eichhorn ; Rosa Ló ; pez ; Vicente Garcí ; a-Gonzá ; lez ; Richard Roberts ; Montserrat Miralpeix
• 关键词：cAMP ; cyclic adenosine monophosphate ; CHO ; chinese hamster ovary cell line ; CRTh2 ; chemoattractant receptor-homologous molecule expressed on T-helper cells ; DK-PGD2 ; 13-14-dihydro-15-keto-PGD2 ; GDP ; guanosine diphosphate ; GPCR ; G protein-coupled receptor ; GTP ; guanosine triphosphate ; PGD2 ; prostaglandin D2 ; PMN ; polymorphonuclear cells ; Th2 ; T-helper cells type 2
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：111
• 期：Complete
• 页码：208-216
• 全文大小：1736 K

文摘

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 21 h 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.