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

详细信息    查看全文

• 作者：Haiping Zhou ; Qihua Zhu ; Zongjie Gan ; Guangping Dong…
• 关键词：Anti ; allergic agents ; Laropiprant derivatives ; Synthesis ; Flushing ; Biological evaluation
• 刊名：Medicinal Chemistry Research
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：24
• 期：11
• 页码：3920-3931
• 全文大小：578 KB
• 参考文献：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 6:235-43CrossRef PubMed
  Boie Y, Sawyer N, Slipetz DM, Metters KM, Abramovitz M (1995) Molecular cloning and characterization of the human prostanoid DP receptor. J Biol Chem 270:18910-8916CrossRef PubMed
  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 103:6682-687PubMed Central CrossRef PubMed
  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 91:11192-1196PubMed Central CrossRef PubMed
  Kabashima K, Narumiya S (2003) The DP receptor, allergic inflammation and asthma. Prostaglandins Leukot Essent Fatty Acids 69:187-94CrossRef PubMed
  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 110:817-22CrossRef PubMed
  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 126:2637-646CrossRef PubMed
  Maicas N, Ibá?ez L, Alcaraz MJ, úbeda A, Ferrándiz ML (2012) Prostaglandin D2 regulates joint inflammation and destruction in murine collagen-induced arthritis. Arthritis Rheum 64:130-40CrossRef PubMed
  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 287:2013-017CrossRef PubMed
  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 4:105-12CrossRef PubMed
  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 69:1665-679CrossRef PubMed
  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 6:313-25CrossRef PubMed
  Sanyal S, Kuvin JT, Karas RH (2010) Niacin and laropiprant. Drugs Today (Barc) 46:371-78CrossRef
  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 50:794-06CrossRef PubMed
  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 63:135-41CrossRef PubMed
  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 377:101-15CrossRef PubMed
  
• 作者单位：Haiping Zhou (1)
  Qihua Zhu (1)
  Zongjie Gan (2)
  Guangping Dong (2)
  Yungen Xu (1) (2)
  
  1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China
  2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
• 出版者：Springer US
• ISSN：1554-8120

文摘

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-strong class="EmphasisTypeBold ">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. Keywords Anti-allergic agents Laropiprant derivatives Synthesis Flushing Biological evaluation