Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist

Fretz, Heinz; Valdenaire, Anja; Pothier, Julien; Hilpert, Kurt; Gnerre, Carmela; Peter, Oliver; Leroy, Xavier; Riederer, Markus A.

doi:10.1021/jm400122f

Cited by 39 publications

(28 citation statements)

References 34 publications

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“…In vitro models have shown that setipiprant effectively blocks PGD 2 ‐induced activation of eosinophils and basophils, cytokine release by PGD 2 ‐stimulated human Th2‐cells, and eosinophil migration towards PGD 2 . Inhibition of PGD2‐chemotactic eosinophil migration was also demonstrated in a rat model of lung eosinophilia . In a previous phase I study in healthy subjects, setipiprant was well tolerated after single and multiple daily doses up to and including 2000 mg and 1000 mg b.i.d ., respectively .…”

Section: Introductionmentioning

confidence: 80%

Setipiprant, a selective CRTH2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics

Diamant

Sidharta

Singh

et al. 2014

Clin Experimental Allergy

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Section: Introductionmentioning

confidence: 80%

Setipiprant, a selective CRTH2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics

Diamant

Sidharta

Singh

et al. 2014

Clin Experimental Allergy

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“…In Part A, plasma samples were taken predose on Day 1 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 13, 18, 24, 36 and 48 h after drug intake. In Part B, plasma samples were collected immediately prior to first dose on Day 1, 0.5, 1, 1.5, 2, 3, 4, 5, 6 and 9 h postmorning dose on Day 1, predose starting from Day 1 evening administration up to Day 6 morning administration and 0.5, 1, 1.5, 2, 3, 4, 5, 6,9,12,14,20,24,36 and 48 h postmorning dose on Day 6.…”

Section: Pharmacokinetic Assessmentsmentioning

confidence: 99%

Single‐ and multiple‐dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects

Sidharta

Diamant

Dingemanse

2014

Fundamemntal Clinical Pharma

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Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders.

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“…To the date of reporting, three CRTH2 antagonists have been tested in phase II trials, i.e. NAV-QAV680, which showed good bioavailability in rats and rodents [87], setipiprant [2-(2-[1-naphthoyl]-8-fluoro-3,4-dihydro-1H-pyrido(4, 3-b)indol-5[2H]-yl)acetic acid] [88], and ARRY-502.…”

Section: Drugs Targeting Crth2 and Crth2/dprmentioning

confidence: 99%

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

Heck¹,

Nguyen

Le³

et al. 2015

Int Arch Allergy Immunol

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Bronchial asthma is a heterogeneous, complex, chronic inflammatory and obstructive pulmonary disease driven by various pathways to present with different phenotypes. A small proportion of asthmatics (5-10%) suffer from severe asthma with symptoms that cannot be controlled by guideline therapy with high doses of inhaled steroids plus a second controller, such as long-acting β₂ agonists (LABA) or leukotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new therapeutic avenues for asthma treatment. The approval of the humanized anti-IgE antibody omalizumab for the treatment of severe allergic asthma has paved the way for other cytokine-targeting therapies, particularly those targeting interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithelium-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the development of novel biologicals that target a diverse array of phenotype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeutic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel therapies for severe asthma.

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Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist

Cited by 39 publications

References 34 publications

Setipiprant, a selective CRTH2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics

Setipiprant, a selective CRTH2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics

Single‐ and multiple‐dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

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