双药效团分子治疗COPD的研究进展
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摘要
慢性阻塞性肺病(COPD)愈来愈威胁人类的健康,发病时会出现多种病理反应,目前现有的治疗药物很难单独改善发病症状,需要联合用药。近年来,研究发展了一些在同一个分子中含有两种或两种以上的药效团的药物分子,这些药效团在体内可同时发挥作用,延长作用时间,减轻疾病症状。本文从药物分子设计、构效关系研究和药理活性分析等方面对双药效团分子治疗COPD的研究进展进行总结。
Chronic obstructive pulmonary disease(COPD) has threatened human health in an increasingly fierce manner. Since there are various pathologic responses during the onset,available drug treatments have difficulties to relieve the symptoms alone,and therefore need to be used jointly. In recent years,studies have discovered that the same molecule containing two or more pharmacophores will have them work together in the body,extending the functioning time and reducing the symptoms comprehensively. This reviewdiscusses the research progress of treatments for COPD from perspectives of molecular drug design,structure-activity relationships and pharmacological activity analysis.
Chronic obstructive pulmonary disease(COPD) has threatened human health in an increasingly fierce manner. Since there are various pathologic responses during the onset,available drug treatments have difficulties to relieve the symptoms alone,and therefore need to be used jointly. In recent years,studies have discovered that the same molecule containing two or more pharmacophores will have them work together in the body,extending the functioning time and reducing the symptoms comprehensively. This reviewdiscusses the research progress of treatments for COPD from perspectives of molecular drug design,structure-activity relationships and pharmacological activity analysis.
引文
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[18] BAUR F,BEATTIE D,BEER D,et al. The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist[J]. J M ed Chem,2010,53(9):3675-3684.
[19] PANAYIOTIS A,VICTORA J,NICOLA J,et al.Synthesis and structure-activity relationships of longactingβ2adrenergic receptor agonists incorporating arylsulfonamide groups[J]. J M ed Chem,2009,52(9):2280-2288.
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[21] JONES L H,RANDALL A,NAPIER C,et al.Design and synthesis of a fluorescent muscarinic antagonist[J]. Bioorg M ed Chem Lett,2008,18(2):825-827.
[22] JONES L H,BALDOCK H,BUNNAGE M E,et al.Inhalation by design:dual pharmacology beta-2 agonists/M3 antagonists for the treatment of COPD[J].Bioorg M ed Chem Lett,2011,21(9):2759-2763.
[23] KEMP J A. New cyclohexylamine derivatives havingβ2aderengic agonist and M3 muscarinic antagonist activities:WO,2011141180[P]. 2011-11-17.
[24] ASHOUR A,SHARKAWY S,AMER M,et al. Rational design and synthesis of topoisomeraseⅠandⅡinhibitors based on oleanolic acid moiety for new anti-cancer drugs[J]. Bioorg M ed Chem,2014,22(1):211-220.
[25] OSBORNE R,CLARKE N,GLOSSOP P,et al. Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonistbeta(2)-agonist for the treatment of chronic obstructive pulmonary disease[J]. J M ed Chem,2011,54(19):6998-7002.
[26] DRAMANE I,LAINE B M,SONIA T,et al. Discovery of novel 1-azoniabicyclo[2. 2. 2]octane muscarinic acetylcholine receptor antagonists[J]. J M ed Chem,2009,52(8):2493-2505.
[27] CARTER J,LALITA N B,VICKI H A,et al. Analogues of oxybutynin. Synthesis and antimuscarinic and bladder activity of some substituted 7-amino-lhydroxy-5-heptyn-2-ones and related compounds[J]. J Med Chem,1991,34(10):3065-3074.
[28] ASTRAZENECA A B. Pulmagen therapeutics(Synergy)Ltd. New combinations for the treatment of asthma:WO,2011012897[P]. 2012-11-01.
[29] CHIESI FARMACEUTICI A. Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity:WO,2012168349[P].2012-12-13.
[30] TEIJIN PHARMA Ltd. Quaternary ammonium salt compound:WO,2010126025[P]. 2012-11-01.
[31] SHAN W J,HUANG L,ZHOU Q,et al. Dual beta2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD[J]. Bioorg M ed Chem Lett,2012,22(4):1523-1526.
[32] LIU A Q,HUANG L,WANG Z R,et al. Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone:dual beta(2)-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD[J]. Bioorg M ed Chem Lett,2013,23(5):1548-1552.
[33] HUANG L,SHAN W J,ZHOU Q,et al. Design,synthesis and evaluation of dual pharmacology beta2-adrenoceptor agonists and PDE4 inhibitors[J].Bioorg M ed Chem Lett,2014,24(1):249-253.
[34] PROVINS L,CHRISTOPHE B,DANHAIVE P,et al.Dual M3 antagonists-PDE4 inhibitors. Part 2:synthesis and SAR of 3-substituted azetidinyl derivatives[J].Bioorg Med Chem Lett,2007,17(11):3077-3080.
[2] HUGHES A D,CHIN K,DUNHAM S L,et al. Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist(M ABA)dual pharmacology molecules[J]. Bioorg M ed Chem Lett,2011,21(5):1354-1358.
[3] World Health Organization. Chronic obstructive pulmonary disease[EB/OL].[2013-10-08].http://w w w. w ho. int/respiratory/copd/en/.
[4] CALVERLEY P M A,ANDERSON J A,BARTOLOM E C,et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease[J]. N Engl J M ed,2007,356(8):775-789.
[5] CALVERLEY P M,BOONSAWAT W,CSEKE Z,et al. M aintenance therapy w ith budesonide and formoterol in chronic obstructive pulmonary disease[J].Eur Respir J,2003,22(6):912-919.
[6] PROVINS L,CHRISTOPHE B,DANHAIVE P,et al. First dual M3 antagonists-PDE4 inhibitors:synthesis and SAR of 4,6-diaminopyrimidine derivatives[J]. Bioorg Med Chem Lett,2006,16(7):1834-1839.
[7] CASHMAN J R,VOELKER T,ZHANG H T,et al.Dual inhibitors of phosphodiesterase-4 and serotonin reuptake[J]. J M ed Chem,2009,52(6):1530-1539.
[8] KETABCHY M,SAMPLE J,THOMPSON T,et al.Thermal evaluation of urbanization using a hybrid approach[J]. J Environ M anage,20018,226(15):457-475.
[9] GROSS N. Ipratropium bromide[J]. N Engl J Med,1988,319(8):480-486.
[10] AHRENS R C,SMITH G D. Albuterol:an adrenergic agent for use in the treatment of asthma pharmacology,pharmacokinetics and clinical use[J]. Pharmacotherapy,1984,4(3):105-121.
[11] NORMAN P. New dual-acting bronchodilator treatments for COPD,muscarinic antagonists and beta2agonists in combination or combined into a single molecule[J]. Expert Opin Investig Drugs,2013,22(12):1569-1580.
[12] RAY N C,ALCARAZ L. Muscarinic antagonistbeta-adrenergic agonist dual pharmacology molecules as bronchodilators:a patent review[J]. Expert Opin Ther Pat,2009,19(1):1-12.
[13] BABU K S,MORJARIA J B. Emerging therapeutic strategies in COPD[J]. Drug Discov Today,2015,20(3):371-379.
[14] FITZGERALD M F,FOX J C. Emerging trends in the therapy of COPD:bronchodilators as mono-and combination therapies[J]. Drug Discov Today,2007,12(11/12):472-478.
[15] MAMMEN M,JI Y H,MU Y,et al. Biphenyl compounds useful as muscarinic receptor antagonists:US,7456199[P]. 2005-09-15.
[16] NAITO R,TAKEUCHI M,MORIHIRA K,et al. Selective muscarinic antagonists.Ⅱ. Synthesis and antimuscarinic properties of biphenylylcarbamate derivatives[J]. Chem Pharm Bull,1998,46(8):1286-1294.
[17] BEATTIE D,BEER D,BRADLEY M E,et al. An investigation into the structure-activity relationships associated w ith the systematic modification of the beta(2)-adrenoceptor agonist indacaterol[J]. Bioorg M ed Chem Lett,2012,22(19):6280-6285.
[18] BAUR F,BEATTIE D,BEER D,et al. The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist[J]. J M ed Chem,2010,53(9):3675-3684.
[19] PANAYIOTIS A,VICTORA J,NICOLA J,et al.Synthesis and structure-activity relationships of longactingβ2adrenergic receptor agonists incorporating arylsulfonamide groups[J]. J M ed Chem,2009,52(9):2280-2288.
[20] HUGHES A D,CHEN Y,HEGDE S S,et al. Discovery of(R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate(TD-5959,GSK961081,batefenterol):first-in-class dual pharmacology multivalent muscarinic antagonist and beta(2)agonist(M ABA)for the treatment of chronic obstructive pulmonary disease(COPD)[J].J M ed Chem,2015,58(6):2609-2622.
[21] JONES L H,RANDALL A,NAPIER C,et al.Design and synthesis of a fluorescent muscarinic antagonist[J]. Bioorg M ed Chem Lett,2008,18(2):825-827.
[22] JONES L H,BALDOCK H,BUNNAGE M E,et al.Inhalation by design:dual pharmacology beta-2 agonists/M3 antagonists for the treatment of COPD[J].Bioorg M ed Chem Lett,2011,21(9):2759-2763.
[23] KEMP J A. New cyclohexylamine derivatives havingβ2aderengic agonist and M3 muscarinic antagonist activities:WO,2011141180[P]. 2011-11-17.
[24] ASHOUR A,SHARKAWY S,AMER M,et al. Rational design and synthesis of topoisomeraseⅠandⅡinhibitors based on oleanolic acid moiety for new anti-cancer drugs[J]. Bioorg M ed Chem,2014,22(1):211-220.
[25] OSBORNE R,CLARKE N,GLOSSOP P,et al. Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonistbeta(2)-agonist for the treatment of chronic obstructive pulmonary disease[J]. J M ed Chem,2011,54(19):6998-7002.
[26] DRAMANE I,LAINE B M,SONIA T,et al. Discovery of novel 1-azoniabicyclo[2. 2. 2]octane muscarinic acetylcholine receptor antagonists[J]. J M ed Chem,2009,52(8):2493-2505.
[27] CARTER J,LALITA N B,VICKI H A,et al. Analogues of oxybutynin. Synthesis and antimuscarinic and bladder activity of some substituted 7-amino-lhydroxy-5-heptyn-2-ones and related compounds[J]. J Med Chem,1991,34(10):3065-3074.
[28] ASTRAZENECA A B. Pulmagen therapeutics(Synergy)Ltd. New combinations for the treatment of asthma:WO,2011012897[P]. 2012-11-01.
[29] CHIESI FARMACEUTICI A. Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity:WO,2012168349[P].2012-12-13.
[30] TEIJIN PHARMA Ltd. Quaternary ammonium salt compound:WO,2010126025[P]. 2012-11-01.
[31] SHAN W J,HUANG L,ZHOU Q,et al. Dual beta2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD[J]. Bioorg M ed Chem Lett,2012,22(4):1523-1526.
[32] LIU A Q,HUANG L,WANG Z R,et al. Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone:dual beta(2)-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD[J]. Bioorg M ed Chem Lett,2013,23(5):1548-1552.
[33] HUANG L,SHAN W J,ZHOU Q,et al. Design,synthesis and evaluation of dual pharmacology beta2-adrenoceptor agonists and PDE4 inhibitors[J].Bioorg M ed Chem Lett,2014,24(1):249-253.
[34] PROVINS L,CHRISTOPHE B,DANHAIVE P,et al.Dual M3 antagonists-PDE4 inhibitors. Part 2:synthesis and SAR of 3-substituted azetidinyl derivatives[J].Bioorg Med Chem Lett,2007,17(11):3077-3080.