Biochemical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asthma

British Journal of Pharmacology

Volumn 168, Issue 7, 2013, Pages 1626-1638

  Schmidt, J A ^a,d   Bell, F M ^a   Akam, E ^a   Marshall, C ^a   Dainty, I A ^b   Heinemann, A ^c   Dougall, I G ^a,d   Bonnert, R V ^a   Sargent, C A ^a,e  

^a ASTRAZENECA   (United Kingdom)

^b ASTRAZENECA R AND D   (Sweden)

^c MEDICAL UNIVERSITY OF GRAZ   (Austria)

^d Burton on the Wolds ^*  (United Kingdom)

^e Burton on the Wolds   (United Kingdom)

Author keywords

asthma; AZD1981

Indexed keywords

4 (ACETYLAMINO) 3 [(4 CHLOROPHENYL)THIO] 2 METHYL 1H INDOLE 1 ACETIC ACID; ANTIASTHMATIC AGENT; AZD 1981; CD11B ANTIGEN; CHEMOATTRACTANT; G PROTEIN COUPLED RECEPTOR; PROSTAGLANDIN D; PROSTAGLANDIN D2; PROSTAGLANDIN RECEPTOR BLOCKING AGENT; PROTEIN DP2; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; ASTHMA; BASOPHIL; CELL MIGRATION; CELL SHAPE; CHEMICAL ANALYSIS; CHEMOTAXIS; CLINICAL EVALUATION; CONTROLLED STUDY; DOG; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; EOSINOPHIL; GUINEA PIG; HUMAN; HUMAN CELL; NONHUMAN; PHARMACODYNAMICS; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RABBIT; TH2 CELL; TREATMENT RESPONSE; UPREGULATION;

EID: 84875141481     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12053     Document Type: Article

References (61)

1. Abe H, Takeshita T, Nagata K, Arita T, Endo Y, Fujita T, et al,. (1999). Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. Gene 227: 71-77.
2. th Edition. Br J Phamacol 164 (Suppl. 1): S1-S324.
3. Angeli V, Staumont D, Charbonnier AS, Hammad H, Gosset P, Pichavant M, et al,. (2004). Activation of the D prostanoid receptor 1 regulates immune and skin allergic responses. J Immunol 172: 3822-3829.
4. Anhut H, Peskar BA, Bernauer W, (1978). Release of 15-keto-13,14-dihydro- thromboxane B2 and prostaglandin D 2 during anaphylaxis as measured by radioimmunoassay. Naunyn Schmiedebergs Arch Pharmacol 305: 247-252.
5. Arimura A, (2010). Discovery of a First-in-Class Drug, a Prostaglandin D2 Antagonist, for the Treatment of Allergic Diseases. Molecular Imaging for Integrated Medical Therapy and Drug Development Part IV, pp. 281-287.
6. Balzar S, Fajt ML, Comhair SA, Erzurum SC, Bleecker E, Busse WW, et al,. (2011). Mast cell phenotype, location and activation in severe asthma, data from the Severe Asthma Research Program. Am J Respir Crit Care Med 183: 299-309.
7. Banfield C, Parnes J, Emery M, Ni L, Zhang N, Hodsman P, (2010). Single-dose, first-in-human study of AMG 853: pharmacokinetics, pharmacodynamics, and safety in healthy adults. Am J Respir Crit Care Med 181: A5397.
8. Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, et al,. (2012). A randomised, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy 42: 38-48.
9. Barski OA, Tipparaju SM, Bhatnagar A, (2008). The aldo-keto reductase superfamily and its role in drug metabolism and detoxification. Drug Metab Rev 40: 553-624.
10. 2 (DP2) receptor antagonists. Bioorg Med Chem Lett 16: 4287-4290.
11. Black JW, Leff P, (1983). Operational models of pharmacological agonism. Proc Royal Soc Biol 84: 141-162.
12. 2 receptor ligands for the treatment of respiratory disorders. PCT Int Appl WO2004106302.
13. 2. Br J Pharmacol 3: 102P.
14. Chaudhry PS, Cabrera J, Juliani HR, Varma SD, (1983). Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol 32: 1995-1998.
15. Cheng Y-C, Prusoff WH, (1973). Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22: 3099-3108.
16. Chevalier E, Stock J, Fisher T, Dupont M, Fric M, Fargeau H, et al,. (2005). Cutting edge: chemoattractant receptor-homologous molecule expressed on Th2 cells plays a restricting role on IL-5 production and eosinophil recruitment. J Immunol 175: 2056-2060.
17. Crea AE, Nakhosteen JA, Lee TH, (1992). Mediator concentrations in bronchoalveolar lavage fluid of patients with mild asymptomatic bronchial asthma. Eur Respir J 5: 190-195.
18. Foster PS, (1999). Allergic networks regulating eosinophilia. Am J Respir Cell Mol Biol 21: 451-454.
19. 2 receptors CRTH2 and DP. J Allergy Clin Immunol 108: 982-988.
20. Gervais FG, Sawyer N, Stocco R, Hamel M, Krawczyk C, Sillaots S, et al,. (2011). Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. Mol Pharmacol 79: 69-76.
21. + Th2 lymphocytes in response to mast cell supernatants. Immunology 119: 362-368.
22. 2, causes eosinophil mobilization from the bone marrow and primes eosinophils for chemotaxis. J Immunol 170: 4752-4758.
23. 2. J Exp Med 193: 255-261.
24. 2 receptor, CRTH2. J Immunol 168: 981-985.
25. Horak F, Toth J, Hirschwehr R, Marks B, Stubner UP, Jager S, et al,. (1998). Effect of continuous allergen challenge on clinical symptoms and mediator release in dust-mite-allergic patients. Allergy 53: 68-72.
26. Jin Y, Penning TM, (2007). Aldo-keto reductases and bioactivation/ detoxication. Annu Rev Pharmacol Toxicol 47: 263-292.
27. Kenakin TP, (2009). Orthosteric drug antagonism. In:, Kenakin TP, (ed.). A Pharmacology Primer: Theory, Applications and Methods, 3rd edn. Elsevier Academic Press: Burlington, MA, pp. 101-127.
28. 2 generation after activation of rat and human mast cells with anti-IgE. J Immunol 129: 1627-1631.
29. 2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Respir Dis 142: 126-132.
30. Lukacs NW, Berlin AA, Franz-Bacon K, Sásik R, Sprague LJ, Ly TW, et al,. (2008). CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation. Am J Physiol Lung Cell Mol Physiol 295: L767-L779.
31. 2 antagonists-discovery of AZD1981. Bioorg Med Chem Lett 21: 6288-6292.
32. Marshall C, Sargent C, Young S, Barker J, (2005). Is there a CRTH2 functional response in the dog? Br J Pharmacol (Winter Meeting) 3: 103P. Available at: http://www.pa2online.org/abstract/abstract.jsp?abid= 28258&author=Sargent&cat=-1&period=23 (accessed 6/12/12).
33. 2 in the dog. Am J Respir Crit Care Med 3 (abstract issue): A584.
34. Mathiesen JM, Christopoulos A, Ulven T, Royer JF, Campillo M, Heinemann A, et al,. (2006). On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2. Mol Pharmacol 69: 1441-1453.
35. 2 as a mediator of allergic asthma. Science 287: 2013-2017.
36. 2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor. Blood 98: 1942-1948.
37. 2/DP2 in human eosinophils. J Pharmacol Exp Ther 304: 349-355.
38. 2 into human airways during acute antigen challenge. N Engl J Med 315: 800-804.
39. 2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s). FEBS Lett 459: 195-199.
40. Nagata K, Tanaka K, Ogawa K, Kemmotsu K, Imai T, Yoshie O, (1999b). Selective expression of a novel surface molecule by human Th2 cells in vivo. J Immunol 162: 1278-1286.
41. 2 receptor antagonists in development. Exp Opin Invest Drugs 19: 947-961.
42. 2 in BAL fluid after methacholine challenge in asthmatic subjects. Eur Respir J 6: 405-412.
43. Petrash JM, (2004). All in the family: aldose reductase and closely related aldo-keto reductases. Cell Mol Life Sci 61: 737-749.
44. 2 receptor CRTH2. Drug News Perspect 21: 317-322.
45. Pettipher R, Whittaker M, (2012). Update on the development of antagonists of chemoattractant receptor-homologous molecule expressed on Th2 Cells (CRTH2). From lead optimization to clinical proof-of-concept in asthma and allergic rhinitis. J Med Chem 55: 2915-2931.
46. Philip G, van Adelsberg J, Loeys T, Liu N, Wong P, Lai E, et al,. (2009). Clinical studies of the DP1 antagonist laropiprant in asthma and allergic rhinitis. J Allergy Clin Immunol 124: 942-948.
47. 2 blocks the locomotion of eosinophils and basophils. Eur J Clin Invest 38: 663-671.
48. Sanyal S, Kuvin JT, Karas RH, (2010). Niacin and laropiprant. Drugs Today (Barc) 46: 371-378.
49. Satoh T, Moroi R, Aritake K, Urade Y, Kanai Y, Sumi K, et al,. (2006). Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor. J Immunol 177: 2621-2629.
50. Schuligoi R, Sturm E, Luschnig P, Konya V, Philipose S, Sedej M, et al,. (2010). CRTH2 and d-type prostanoid receptor antagonists as novel therapeutic agents for inflammatory diseases. Pharmacology 85: 372-382.
51. Singh D, Cadden P, Hunter M, Collins LP, Perkins M, Pettipher R, et al,. (2012). Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J (Epub April 2012).
52. 2 receptor DP2/CRTH2 increases allergic inflammation in mouse. J Immunol 174: 3703-3708.
53. Stebbins KJ, Broadhead AR, Correa LD, Scott JM, Truong YP, Stearns BA, et al,. (2010). Therapeutic efficacy of AM156, a novel prostanoid DP2 receptor antagonist, in murine models of allergic rhinitis and house dust mite-induced pulmonary inflammation. Eur J Pharmacol 638: 142-149.
54. Stubbs VE, Schratl P, Hartnell A, Williams TJ, Peskar BA, Heinemann A, et al,. (2002). Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils. J Biol Chem 277: 26012-26020.
55. 2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respir Res 8: 16-25.
56. Ulven T, Kostenis E, (2010). Novel CRTH2 antagonists: a review of patents from 2006 to 2009. Exp Opin Ther Patents 20: 1505-1530.
57. Ulven T, Receveur J-M, Grimstrup M, Rist O, Frimurer TM, Gerlach L-O, et al,. (2006). Novel selective orally active CRTH2 antagonists for allergic inflammation developed from in silico derived hits. J Med Chem 49: 6638-6641.
58. Wenzel SE, Westcott JY, Smith HR, Larsen GL, (1989). Spectrum of prostanoid release after bronchoalveolar allergen challenge in atopic asthmatics and in control groups. An alteration in the ratio of bronchoconstrictive to bronchoprotective mediators. Am Rev Respir Dis 139: 450-457.
59. Xue L, Gyles SL, Wettey FR, Gazi L, Townsend E, Hunter MG, et al,. (2005). Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells. J Immunol 175: 6531-6536.
60. Xue L, Barrow A, Pettipher R, (2009a). Interaction between prostaglandin D and chemoattractant receptor-homologous molecule expressed on Th2 cells mediates cytokine production by Th2 lymphocytes in response to activated mast cells. Clin Exp Immunol 156: 126-133.
61. Xue L, Barrow A, Pettipher R, (2009b). Novel function of CRTH2 in preventing apoptosis of human Th2 cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol 182: 7580-7586.