Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy.

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [(3)H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.

Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human β2 Adrenoceptor.

Super agonists produce greater functional responses than endogenous agonists in the same assay, and their unique pharmacology is the subject of increasing interest and debate. We propose that receptor residence time and the duration of receptor signaling contribute to the pharmacology of super agonism. We have further characterized the novel β2 adrenoceptor agonist C26 (7-[(R)-2-((1R,2R)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone), which displays higher intrinsic activity than the endogenous ligand adrenaline in cAMP accumulation, β-arrestin-2 recruitment, and receptor internalization assays.

Functional desensitization of the β 2 adrenoceptor is not dependent on agonist efficacy.

Chronic treatment with β 2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure.

Investigating the molecular mechanisms through which FTY720-P causes persistent S1P1 receptor internalization.

Background And Purpose: The molecular mechanism underlying the clinical efficacy of FTY720-P is thought to involve persistent internalization and enhanced degradation of the S1P1 receptor subtype (S1P1R). We have investigated whether receptor binding kinetics and β-arrestin recruitment could play a role in the persistent internalization of the S1P1R by FTY720-P.

Experimental Approach: [(3) H]-FTY720-P and [(33) P]-S1P were used to label CHO-S1P1/3Rs for binding studies.

An investigation into the structure-activity relationships associated with the systematic modification of the β(2)-adrenoceptor agonist indacaterol.

The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the β(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical β(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.

The in vitro metabolism of sphingosine-1-phosphate: identification; inhibition and pharmacological implications.

A time-dependent decrease in S1P potency was observed in a [(35)S]-GTPγS binding assay using CHO-cell membranes expressing the human S1P(2) receptor. After a three hour incubation with membranes the pEC(50) of S1P was 7.09 ± 0.