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Crth2 antagonist

Piotr Kuna, Leif Bjermer, Göran Tornling
BACKGROUND: Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma. OBJECTIVES: The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control. PATIENTS AND METHODS: Adults aged 18-60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510])...
2016: Drug Design, Development and Therapy
Ken Grime, Rikard Pehrson, Pär Nordell, Michael Gillen, Wolfgang Kühn, Timothy Mant, Marie Brännström, Petter Svanberg, Barry Jones, Clive Brealey
AIM: AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug-drug interaction (DDI) and on a clinical warfarin DDI study...
August 24, 2016: British Journal of Clinical Pharmacology
Yusuke Onaka, Norihito Shintani, Takanobu Nakazawa, Takuya Kanoh, Yukio Ago, Toshio Matsuda, Ryota Hashimoto, Kazutaka Ohi, Hiroyuki Hirai, Kin-Ya Nagata, Masataka Nakamura, Atsushi Kasai, Atsuko Hayata-Takano, Kazuki Nagayasu, Kazuhiro Takuma, Asao Ogawa, Akemichi Baba, Hitoshi Hashimoto
Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), which is a second receptor for prostaglandin (PG) D2, is involved in inflammatory responses in peripheral tissue; however, its role in cognitive function remains unclear. Here, we demonstrate that CRTH2 is involved in cognitive function using a well-established animal model of cognitive dysfunction induced by MK-801, an N-methyl-d-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitive dysfunction...
November 1, 2016: Behavioural Brain Research
Ibrahim Sulaiman, Jonathan Chee Woei Lim, Hon Liong Soo, Johnson Stanslas
Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs...
October 2016: Pulmonary Pharmacology & Therapeutics
Pierachille Santus, Dejan Radovanovic
INTRODUCTION: Asthma is a chronic inflammatory disease characterized by bronchial hyper-reactivity. Although many currently available treatment regimens are effective, poor symptom control and refractory severe disease still represent major unmet needs. In the last years, numerous molecular therapeutic targets that interfere with the innate inflammatory response in asthma have been identified. Promising preliminary results concern the signaling cascade promoted by prostaglandin D2 (PGD2) and its receptor antagonists...
September 2016: Expert Opinion on Investigational Drugs
Veit J Erpenbeck, Todor A Popov, David Miller, Steven F Weinstein, Sheldon Spector, Baldur Magnusson, Wande Osuntokun, Paul Goldsmith, Markus Weiss, Jutta Beier
BACKGROUND: There is an unmet medical need for allergic asthma patients who are uncontrolled on conventional therapies. The aim of this study was to collect efficacy and safety data for QAW039, an oral chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist, for the treatment of asthma. METHODS: This was an exploratory phase II, double-blind, randomized, placebo-controlled multi-center study. Patients with mild-to-moderate uncontrolled allergic asthma (N = 170) were either without or weaned off inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) and randomized (1:1) to QAW039 (500 mg once daily) or to placebo for 28 days...
August 2016: Pulmonary Pharmacology & Therapeutics
Marta Calbet, Miriam Andrés, Clara Armengol, Mónica Bravo, Peter Eichhorn, Rosa López, Vicente García-González, Richard Roberts, Montserrat Miralpeix
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...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Veit J Erpenbeck, Eva Vets, Lien Gheyle, Wande Osuntokun, Michael Larbig, Srikanth Neelakantham, David Sandham, Gerald Dubois, Walid Elbast, Paul Goldsmith, Markus Weiss
We evaluated the pharmacokinetics (PK), safety, and tolerability of a novel oral CRTh2 antagonist, fevipiprant (QAW039), in healthy subjects. Peak concentrations of fevipiprant in plasma were observed 1-3 hours postdosing. Concentrations declined in a multiexponential manner, followed by an apparent terminal phase (t1/2 , ∼20 hours). Steady state was achieved in 4 days with <2-fold accumulation. Elimination was partly by renal excretion (≤30% of the dose) and glucuronidation. Food had minimal impact on the PK of fevipiprant, and it was well tolerated at single and multiple oral doses up to 500 mg/day...
July 2016: Clinical Pharmacology in Drug Development
Kengo Kanai, Mitsuhiro Okano, Tazuko Fujiwara, Shin Kariya, Takenori Haruna, Ryotaro Omichi, Sei-Ichiro Makihara, Yuji Hirata, Kazunori Nishizaki
BACKGROUND: Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E2 induces VEGF release by nasal polyp fibroblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD2 metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production...
April 15, 2016: Allergology International: Official Journal of the Japanese Society of Allergology
Nesrine Kamal Bassal, Bernard P Hughes, Maurizio Costabile
Expression of elevated levels of Indoleamine 2,3-dioxygenase (IDO) is well established as a mechanism of cancer induced immunosuppression. Pharmacological inhibition of IDO activity is thus a promising alternative in the treatment of cancer. Previously we demonstrated that cyclooxygenase derived metabolites of arachidonic acid inhibited the interferon-gamma mediated induction of IDO in both THP-1 cells and human monocytes. Here we identified that of the five primary prostanoids produced by COX-1/COX-2, only PGD2 displayed significant repressor activity...
July 2016: Prostaglandins, Leukotrienes, and Essential Fatty Acids
Balázs Radnai, Eva M Sturm, Angela Stančić, Katharina Jandl, Sandra Labocha, Nerea Ferreirós, Magdalena Grill, Carina Hasenoehrl, Gregor Gorkiewicz, Gunther Marsche, Ákos Heinemann, Christoph Högenauer, Rudolf Schicho
BACKGROUND AND AIMS: Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors. METHODS: Using the 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment...
September 2016: Journal of Crohn's & Colitis
Maria Antonia Buil, Marta Calbet, Marcos Castillo, Jordi Castro, Cristina Esteve, Manel Ferrer, Pilar Forns, Jacob González, Sara López, Richard S Roberts, Sara Sevilla, Bernat Vidal, Laura Vidal, Pere Vilaseca
Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times...
May 4, 2016: European Journal of Medicinal Chemistry
David A Sykes, Michelle E Bradley, Darren M Riddy, Elizabeth Willard, John Reilly, Asadh Miah, Carsten Bauer, Simon J Watson, David A Sandham, Gerald Dubois, Steven J Charlton
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 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2(PGD2)...
May 2016: Molecular Pharmacology
Hidekazu Saito, Kohei Honda, Chikara Asaka, Shigeharu Ueki, Kazuo Ishikawa
BACKGROUND: The chemokine receptor, CC-chemokine receptor 3 (CCR3), and its major ligands, eotaxin, RANTES, and MCP-4, are involved in eosinophil chemotaxis. It is thought that CCR3 plays an important role in the recruitment and activation of eosinophils in nasal polyposis. We examined nasal polyp extract-induced eosinophil chemotaxis and the effect of a CCR3 antagonist using EZ-TAXIScan, a novel real-time chemotaxis assay device. METHODS: Nasal polyps were obtained from chronic rhinosinusitis (CRS) patients during surgery...
July 2016: Allergology International: Official Journal of the Japanese Society of Allergology
Andreas Krause, Jochen Zisowsky, Daniel S Strasser, Martine Gehin, Patricia N Sidharta, Peter M A Groenen, Jasper Dingemanse
BACKGROUND AND OBJECTIVE: The chemoattractant receptor-homologous molecule expressed on T helper-2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders. Two selective and potent CRTH2 antagonists currently in clinical development, ACT-453859 and setipiprant, were compared with respect to their (predicted) clinical efficacy. METHODS: Population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to characterize how plasma concentrations (PK) of ACT-453859, its active metabolite ACT-463036 and setipiprant related to their effect on blocking PGD2-induced internalization of CRTH2 on eosinophils (PD)...
July 2016: Clinical Pharmacokinetics
Kateřina Vávrová
INTRODUCTION: Atopic dermatitis is a chronic, relapsing, pruritic inflammatory skin disease. Both skin barrier defects and abnormal immune reactions contribute to this complex disease. Current therapeutic guidelines recommend the use of moisturizers, good skin care and allergen avoidance as the first-line approach. In patients who do not respond well to these measures, topical corticosteroids, calcineurin inhibitors, and, in severe cases, systemic immunosuppressive agents are mostly used...
2016: Expert Opinion on Therapeutic Patents
Philippe Risch, Thomas Pfeifer, Jerome Segrestaa, Heinz Fretz, Julien Pothier
Various racemic and enantioenriched (trans)-X,Y-dihydroxy-X,Y-dihydronaphthoyl analogues as well as X-hydroxy-naphthoyl analogues of CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1, Setipiprant/ACT-129968) were synthesized in order to gain insight into regio- and enantioselectivity of the metabolic oxidation of 1 and to verify the structures of four metabolites that were proposed earlier in a clinical ADME study. Analytical data of the synthetic standards were compared with data from samples of biological origin...
October 22, 2015: Journal of Medicinal Chemistry
Sathya Babu, Honglae Sohn, Thirumurthy Madhavan
CRTh2 receptor is an important mediator of inflammatory effects and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. In pursuit of better CRTh2 receptor antagonist agents, 3D-QSAR studies were performed on a series of 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl) acetic acids. There is no crystal structure information available on this protein; hence in this work, ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed by atom by atom matching alignment using systematic search and simulated annealing methods...
June 2015: Computational Biology and Chemistry
Y-H Kiang, Karthik Nagapudi, Tian Wu, Matthew L Peterson, Janan Jona, Richard J Staples, Peter W Stephens
Investigation of an additional resonance peak in the (19) F solid-state nuclear magnetic resonance (NMR) spectrum of AMG 853, a dual antagonist of DP and CRTH2 previously in clinical development for asthma, has led to the identification of two conformational isomers coexisting in the crystal lattice in a continuous composition range between 89.7%:10.3% and 96.5%:3.5%. These two isomers differ in the chloro-flurorophenyl moiety orientation-the aromatic ring is flipped by 180° in these two isomers. The level of the minor isomer is directly measured through integration of the two peaks in the (19) F solid-state NMR spectrum...
July 2015: Journal of Pharmaceutical Sciences
Van T Luu, Jean-Yves Goujon, Christian Meisterhans, Matthias Frommherz, Carsten Bauer
The synthesis of a triple tritiated isotopologue of the CRTh2 antagonist NVP-QAW039 (fevipiprant) with a specific activity >3 TBq/mmol is described. Key to the high specific activity is the methylation of a bench-stable dimeric disulfide precursor that is in situ reduced to the corresponding thiol monomer and methylated with [(3)H3]MeONos having per se a high specific activity. The high specific activity of the tritiated active pharmaceutical ingredient obtained by a build-up approach is discussed in the light of the specific activity usually to be expected if hydrogen tritium exchange methods were applied...
May 15, 2015: Journal of Labelled Compounds & Radiopharmaceuticals
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