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Synthesis and biological evaluation of novel laropiprant derivatives as potential anti-allergic agents

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Abstract

DP antagonists are claimed to be useful in the treatment of allergic disorders. Laropiprant is a potent and selective DP antagonist to reduce the allergic disorders, especially niacin-induced flushing. In our study, a series of novel laropiprant derivatives (I-1–I-18) were synthesized and characterized by IR, 1H-NMR, 13C-NMR and HRMS spectrum. The potency of these compounds was evaluated in a murine model of niacin-induced flushing. The results indicated that most compounds exhibited faster-acting effect of suppressing vasodilation than laropiprant. Among them, I-1, I-2, I-3, I-9, I-13, I-15 and I-16 exhibited substantial flushing inhibitory effect. Especially, I-1 and I-2 showed higher potency than laropiprant and would be valuable for further investigation.

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References

  • Ballantyne C, Gleim G, Liu N, Sisk CM, Johnson-Levonas AO, Mitchel Y (2012) Effects of coadministered extended-release niacin/laropiprant and simvastatin on lipoprotein subclasses in patients with dyslipidemia. J Clin Lipidol 6:235–243

    Article  PubMed  Google Scholar 

  • Boie Y, Sawyer N, Slipetz DM, Metters KM, Abramovitz M (1995) Molecular cloning and characterization of the human prostanoid DP receptor. J Biol Chem 270:18910–18916

    Article  CAS  PubMed  Google Scholar 

  • Cheng K, Wu TJ, Wu KK, Sturino C, Metters K, Gottesdiener K, Wright SD, Wang Z, O’Neill G, Lai E, Waters MG (2006) Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. Proc Natl Acad Sci USA 103:6682–6687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hirata M, Kakizuka A, Aizawa M, Ushikubi F, Narumiya S (1994) Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene. Proc Natl Acad Sci USA 91:11192–11196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kabashima K, Narumiya S (2003) The DP receptor, allergic inflammation and asthma. Prostaglandins Leukot Essent Fatty Acids 69:187–194

    Article  CAS  PubMed  Google Scholar 

  • Maccubbin DL, Chen F, Anderson JW, Sirah W, McCrary Sisk C, Kher U, Olsson AG, Bays HE, Mitchel YB (2012) Effectiveness and safety of laropiprant on niacin-induced flushing. Am J Cardiol 110:817–822

    Article  CAS  PubMed  Google Scholar 

  • Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT (2006) Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Investig Dermatol 126:2637–2646

    Article  CAS  PubMed  Google Scholar 

  • Maicas N, Ibáñez L, Alcaraz MJ, Úbeda A, Ferrándiz ML (2012) Prostaglandin D2 regulates joint inflammation and destruction in murine collagen-induced arthritis. Arthritis Rheum 64:130–140

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S (2000) Prostaglandin D2 as a mediator of allergic asthma. Science 287:2013–2017

    Article  CAS  PubMed  Google Scholar 

  • McKenney J, Bays H, Koren M, Ballantyne CM, Paolini JF, Mitchel Y, Betteridge A, Kuznetsova O, Sapre A, Sisk CM, Maccubbin D (2010) Safety of extended-release niacin/laropiprant in patients with dyslipidemia. J Clin Lipidol 4:105–112

    Article  PubMed  Google Scholar 

  • Paolini F, Lai E, Mitchel B (2008) Method of treating atherosclerosis, dyslipidemias and related conditions. WO2008/097535A2

  • Perry CM (2009) Extended-release niacin (nicotinic acid)/laropiprant. Drugs 69:1665–1679

    Article  CAS  PubMed  Google Scholar 

  • Pettipher R, Hansel TT, Armer R (2007) Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov 6:313–325

    Article  CAS  PubMed  Google Scholar 

  • Sanyal S, Kuvin JT, Karas RH (2010) Niacin and laropiprant. Drugs Today (Barc) 46:371–378

    Article  CAS  Google Scholar 

  • Sturino CF, O’Neill G, Lachance N, Boyd M, Berthelette C, Labelle M, Li L, Roy B, Scheigetz J, Tsou N, Aubin Y, Bateman KP, Chauret N, Day SH, Lévesque JF, Seto C, Silva JH, Trimble LA, Carriere MC, Denis D, Greig G, Kargman S, Lamontagne S, Mathieu MC, Sawyer N, Slipetz D, Abraham WM, Jones T, McAuliffe M, Piechuta H, Nicoll-Griffith DA, Wang Z, Zamboni R, Young RN, Metters KM (2007) Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524). J Med Chem 50:794–806

    Article  CAS  PubMed  Google Scholar 

  • Van Hecken A, Depré M, De Lepeleire I, Thach C, Oeyen M, Van Effen J, Laethem T, Mazina K, Crumley T, Wenning L, Gottesdiener KM, Deutsch P, Clement P, Lai E, de Hoon JN (2007) The effect of MK-0524, a prostaglandin D(2) receptor antagonist, on prostaglandin D(2)-induced nasal airway obstruction in healthy volunteers. Eur J Clin Pharmacol 63:135–141

    Article  CAS  PubMed  Google Scholar 

  • Wright DH, Nantel F, Metters KM, Ford-Hutchinson AW (1999) A novel biological role for prostaglandin D2 is suggested by distribution studies of the rat DP prostanoid receptor. Eur J Pharmacol 377:101–115

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the enterprise innovation drug incubation base of the Ministry of Science and Technology, China (No.2012ZX09401-006).

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Authors and Affiliations

  1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China

    Haiping Zhou, Qihua Zhu & Yungen Xu

  2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China

    Zongjie Gan, Guangping Dong & Yungen Xu

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  1. Haiping Zhou
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  2. Qihua Zhu
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  3. Zongjie Gan
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  4. Guangping Dong
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  5. Yungen Xu
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Correspondence to Yungen Xu.

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Zhou, H., Zhu, Q., Gan, Z. et al. Synthesis and biological evaluation of novel laropiprant derivatives as potential anti-allergic agents. Med Chem Res 24, 3920–3931 (2015). https://doi.org/10.1007/s00044-015-1431-8

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  • DOI: https://doi.org/10.1007/s00044-015-1431-8

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