Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti-inflammatory 5-lipoxygenase-activating protein inhibitor

British Journal of Clinical Pharmacology

Volumn 75, Issue 3, 2013, Pages 779-790

  Bain, Gretchen ^a   King, Christopher D ^a   Schaab, Kevin ^b   Rewolinski, Melissa ^b   Norris, Virginia ^c   Ambery, Claire ^c   Bentley, Jane ^c   Yamada, Masanori ^d   Santini, Angelina M ^a   van de Wetering de Rooij, Jeroen ^e   Stock, Nicholas ^f   Zunic, Jasmine ^g   Hutchinson, John H ^g   Evans, Jilly F ^g  

^a BRISTOL MYERS SQUIBB   (United States)

^b INTERCEPT PHARMACEUTICALS   (United States)

^c GLAXOSMITHKLINE   (United Kingdom)

^d Development and Medical Affairs Division   (Japan)

^e PRA Health Sciences   (Netherlands)

^f Current affiliation Inception Sciences Inc   (United States)

^g BrainCells Inc   (United States)

Author keywords

Asthma; FLAP; GSK2190915; Leukotrienes; Pharmacodynamics; Pharmacokinetics

Indexed keywords

FIBOFLAPON; LEUKOTRIENE B4; LEUKOTRIENE E4; PLACEBO;

ABDOMINAL PAIN; ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; BLOOD SAMPLING; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; CROSSOVER PROCEDURE; DRUG ACTIVITY; DRUG DOSE COMPARISON; DRUG ELIMINATION; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DYSPEPSIA; FEMALE; FLATULENCE; FLU LIKE SYNDROME; HEADACHE; HUMAN; INJECTION SITE CONTUSION; INJECTION SITE PAIN; MAJOR CLINICAL STUDY; MALE; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS;

5-LIPOXYGENASE-ACTIVATING PROTEIN INHIBITORS; ADMINISTRATION, ORAL; ADOLESCENT; ADULT; AGED; AREA UNDER CURVE; ASIAN CONTINENTAL ANCESTRY GROUP; BIOLOGICAL MARKERS; CROSS-OVER STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; EUROPEAN CONTINENTAL ANCESTRY GROUP; FEMALE; HUMANS; INDOLES; LEUKOTRIENE B4; LEUKOTRIENE E4; MALE; MIDDLE AGED; PENTANOIC ACIDS; YOUNG ADULT;

EID: 84871558873     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/j.1365-2125.2012.04386.x     Document Type: Article

References (27)

1. Mandal AK, Jones PB, Bair AM, Christmas P, Miller D, Yamin TT, Wisniewski D, Menke J, Evans JF, Hyman BT, Bacskai B, Chen M, Lee DM, Nikolic B, Soberman RJ. The nuclear membrane organization of leukotriene synthesis. Proc Natl Acad Sci U S A 2008; 105: 20434-20439.
2. Miller DK, Gillard JW, Vickers PJ, Sadowski S, Leveille C, Mancini JA, Charleson P, Dixon RA, Ford-Hutchinson AW, Fortin R, Gauthier JY, Rodkey J, Rosen R, Rouzer C, Sigal IS, Strader CD, Evans JF. Identification and isolation of a membrane protein necessary for leukotriene production. Nature 1990; 343: 278-281.
3. Back M. Leukotriene signaling in atherosclerosis and ischemia. Cardiovasc Drugs Ther 2009; 23: 41-48.
4. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SF, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR, Stefansson K. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004; 36: 233-239.
5. Holloway JW, Barton SJ, Holgate ST, Rose-Zerilli MJ, Sayers I. The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility. Allergy 2008; 63: 1046-1053.
6. Via M, De Giacomo A, Corvol H, Eng C, Seibold MA, Gillett C, Galanter J, Sen S, Tcheurekdjian H, Chapela R, Rodriguez-Santana JR, Rodriguez-Cintron W, Thyne S, Avila PC, Choudhry S, Gonzalez Burchard E. The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos. Clin Exp Allergy 2010; 40: 582-589.
7. Dahlen B, Kumlin M, Ihre E, Zetterstrom O, Dahlen SE. Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx 1005. Thorax 1997; 52: 342-347.
8. Diamant Z, Timmers MC, van der Veen H, Friedman BS, De Smet M, Depre M, Hilliard D, Bel EH, Sterk PJ. The effect of MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo. J Allergy Clin Immunol 1995; 95: 42-51.
9. Friedman BS, Bel EH, Buntinx A, Tanaka W, Han YH, Shingo S, Spector R, Sterk P. Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am Rev Respir Dis 1993; 147: 839-844.
10. Berger W, De Chandt MT, Cairns CB. Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract 2007; 61: 663-676.
11. Evans JF, Ferguson AD, Mosley RT, Hutchinson JH. What's all the FLAP about? 5-lipoxygenase-activating protein inhibitors for inflammatory diseases. Trends Pharmacol Sci 2008; 29: 72-78.
12. Storms W. Update on montelukast and its role in the treatment of asthma, allergic rhinitis and exercise-induced bronchoconstriction. Expert Opin Pharmacother 2007; 8: 2173-2187.
13. Price D, Musgrave SD, Shepstone L, Hillyer EV, Sims EJ, Gilbert RF, Juniper EF, Ayres JG, Kemp L, Blyth A, Wilson EC, Wolfe S, Freeman D, Mugford HM, Murdoch J, Harvey I. Leukotriene antagonists as first-line or add-on asthma-controller therapy. N Engl J Med 2011; 364: 1695-1707.
14. Bain G, King CD, Rewolinski M, Schaab K, Santini AM, Shapiro D, Moran M, de Rooij S, Roffel AF, Schuilenga-Hut P, Milne GL, Lorrain DS, Li Y, Arruda JM, Hutchinson JH, Prasit P, Evans JF. Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP). Clin Pharmacol Ther 2010; 87: 437-444.
15. Hutchinson JH, Li Y, Arruda JM, Baccei C, Bain G, Chapman C, Correa L, Darlington J, King CD, Lee C, Lorrain D, Prodanovich P, Rong H, Santini A, Stock N, Prasit P, Evans JF. 5-lipoxygenase-activating protein inhibitors: development of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2 -ylmethoxy)-1H-indol-2-yl]-2, 2-dimethyl-propionic acid (AM103). J Med Chem 2009; 52: 5803-5815.
16. Lorrain DS, Bain G, Correa LD, Chapman C, Broadhead AR, Santini AM, Prodanovich P, Darlington JV, Hutchinson JH, King C, Lee C, Baccei C, Li Y, Arruda JM, Evans JF. Pharmacological characterization of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2 -ylmethoxy)-1H-indol-2-yl]-2, 2-dimethyl-propionic acid (AM103), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation. J Pharmacol Exp Ther 2009; 331: 1042-1050.
17. Lorrain DS, Bain G, Correa LD, Chapman C, Broadhead AR, Santini AM, Prodanovich PP, Darlington JV, Stock NS, Zunic J, King CD, Lee C, Baccei CS, Stearns B, Roppe J, Hutchinson JH, Prasit P, Evans JF. Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation. Eur J Pharmacol 2010; 640: 211-218.
18. Stock N, Baccei C, Bain G, Broadhead A, Chapman C, Darlington J, King C, Lee C, Li Y, Lorrain DS, Prodanovich P, Rong H, Santini A, Zunic J, Evans JF, Hutchinson JH, Prasit P. 5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl- 1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2, 2-dimethyl-propio nic acid (AM679)-a potent FLAP inhibitor. Bioorg Med Chem Lett 2010; 20: 213-217.
19. Sampson AP. FLAP inhibitors for the treatment of inflammatory diseases. Curr Opin Investig Drugs 2009; 10: 1163-1172.
20. Chapman KR, Friedman BS, Shingo S, Heyse J, Relss T, Spector R. The efficacy of an oral inhibitor of leukotriene synthesis (MK-0591) in asthmatics treated with inhaled steroids (abstract). Am J Respir Crit Care Med 1994; 151: A215.
21. Storms W, Friedman BS, Zhang J, Santanello N, Allergar N, Appel D, Beaucher W, Bronsky F, Busse W, Chervinsky P, Dockhorn R, Edwards T, Goldstein M, Grossman J, Hendeles L, Kemp J, Memon N, Nooman M, Owens G, Shapiro G, Spirn I, Strek M, Stricker W, Tinkelman D, Townley R, Wanderer A, Weisberg S, Winder J, Woehler T. Treating asthma by blocking the lipoxygenase pathway (abstract). Am J Respir Crit Care Med 1995; 149: A377.
22. Young RN. Inhibitors of 5-lipoxygenase: a therapeutic potential yet to be fully realized? Eur J Med Chem 1999; 34: 671-685.
23. Depre M, Friedman B, Van Hecken A, de Lepeleire I, Tanaka W, Dallob A, Shingo S, Porras A, Lin C, de Schepper PJ. Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor. Clin Pharmacol Ther 1994; 56: 22-30.
24. Hui KP, Taylor IK, Taylor GW, Rubin P, Kesterson J, Barnes NC, Barnes PJ. Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 1991; 46: 184-189.
25. Kent S, Boyce M, Diamant Z, Singh D, O'Connor B, Sagu P, Norris V. The 5-lipoxygenase activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma. Clin Exp Allergy (in press).
26. Singh D, Richards D, Knowles RG, Schwartz S, Woodcock A, Langley S, O'Connor BJ. Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma. Am J Respir Crit Care Med 2007; 176: 988-993.
27. Adler DH, Cogan JD, Phillips JA, 3rd, Schnetz-Boutaud N, Milne GL, Iverson T, Stein JA, Brenner DA, Morrow JD, Boutaud O, Oates JA. Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J Clin Invest 2008; 118: 2121-2131.