CN102010324B - 阿司匹林触发的脂质介体 - Google Patents
阿司匹林触发的脂质介体 Download PDFInfo
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- CN102010324B CN102010324B CN201010507698.8A CN201010507698A CN102010324B CN 102010324 B CN102010324 B CN 102010324B CN 201010507698 A CN201010507698 A CN 201010507698A CN 102010324 B CN102010324 B CN 102010324B
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Abstract
本发明公开了阿司匹林触发的脂质介体(ATLM),它们可用于治疗或预防与包括缺血在内多种疾病相关的炎症。
Description
本申请是中国专利申请200610100310.6,“阿司匹林触发的脂质介体”的分案申请。
背景技术
过去的25年中,各种报道称:用亚麻籽、加拿大低酸油菜籽油或鱼油通过饮食补充ω-3聚不饱和脂肪酸(w-3 PUFA)对患者和实验室动物有益(1.De Caterian,R.,S.Endres,S.D.Kristensen和E.B.Schmidt编的1993年的n-3脂肪酸和血管疾病,Springer-Verlag,London;和2.Lands,W.E.M.,编的1987年的有关聚不饱和脂肪酸和类花生酸的AOCS短期会议的记录汇编。American Oil Chemists’Society,Champaign,IL)。这些报道中对其潜在的抗血栓、免疫调节、和在动脉硬化、关节炎和哮喘中的抗炎反应,以及抗肿瘤和抗转移等作用有生动的论述(Ref.1和Iigo,M.T.Nakagawa,C.Ishikawa,Y.Iwahori,M.Asamoto,K.Yazawa,E.Araki和H.Tsuda,1997,二十二碳六烯酸抑制结肠癌26向肺部转移的作用。英国癌症杂志,75:650-655)。最近发现,主要的饮食ω-3 PUFA,二十碳五烯酸(C20:5 ω-3;EPA)和二十二碳六烯酸(C22:6 ω-3;DHA)对于局部缺血引起的心室纤维性颤动具有显著效果,而且对狗具有预防心脏病突发性死亡的作用,他们对于心血管病的预防作用因而受到广泛关注(4.Billman,G.E.等,1999,纯ω-3聚不饱和脂肪酸预防狗心脏病突发性死亡的作用。循环,99:2452-2547)。由于发现补充ω-3 PUFA对于婴儿营养、心血管疾病和神经健康可能具有预防和/或治疗作用,所以希望能由某国际专门小组制定出建议饮食摄入量(5.Simopoulus,A.P.等,1999,有关ω-6和ω-3脂肪酸的必要性及其建议饮食摄入量的研讨会记录,J.Am.Coll.Nutr.,18:487-489)。此外,Gruppo Italiano per lo Studio della Sopravvivensenell’Infarto Mocardio(GISSI)Prevenzione试验评价了补充ω-3 PUFA-每日摄入~1g ω-3PUFA-对>11,300曾经心肌梗塞患者的作用,同时推荐了包括阿司匹林的预防治疗,并报道了对于降低心血管病死亡率的显著功效(6.Marchioloi,R.,1999,心肌梗塞后饮食补充n-3聚不饱和脂肪酸和维生素E:GISSI-Prevenzione试验的结果。Gruppo Italianoper lo Studio della Sopravvivense nell’Infarto Mocardio,柳叶刀,354:447-455),然而,迄今为止,包括对神经组织(Parkinson’s病和Alzheimer’s病,以及其他已知的脑部炎症)在内的所有研究中,对于饮食ω-3保护作用的细胞和分子机制都未作出充分的解释。
据信,鱼油中的主要脂质C20:5的作用是基于:(a)阻止花生四烯酸(C20:4 ω-6;AA)转化为促炎性类花生酸(即***素[PGs]和白三烯[LTS);(b)作为另一种底物,生成较弱的5-系列LTS;和/或(c)由环氧合酶(COX)转化为3-系列***素类激素(即PGI3),它们具有与其4-系列PG相当的抗血栓作用(参考文献1,3和4)。包括以上所述的各种解释都没有被普遍接受,因为没有体内分子证据,而体外推定的“有益作用”需要高浓度的ω-3 PUFA(参考文献1-5)。
虽然普遍认同LT和PG具有促炎作用,但有新证据表明:衍生自花生四烯酸酯的其他类花生酸,即脂氧素(LXs),及其内源性类似物,即阿司匹林触发的15-差向异构体LXs(ATLs)是PMN-药物损伤和急性炎症的强反调节剂(counterregulator)(7.Weissmann,G.,1991,阿司匹林,Sci.Am.,264:84-90;8.Marcus,A.J.,1999,血小板:其在止血、血栓和炎症中的作用,炎症:基础原理和临床关联,J.I.Gallin和R.Snyderman编,Lippincott Williams & Wilkins,Philadelphia,77-9;9.Claria,J.和C.N.Serhan,1995,阿司匹林通过人内皮细胞-白细胞相互作用激发了从前描述过的生物活性类花生酸,美国科学院院报,92:9475-9479;10.Serhan,C.N.,J.F.Maddox,N.A.Petasis,I.Akritopoulou-Zanze,A.Papayianni,H.R.Brady,S.P.Colgan和J.L.Madara,1995。可阻止人嗜中性粒细胞迁移和粘附的脂氧素A4稳定类似物,生物化学,34:14609-14615;和11.Chiang,N.,K.Gronert,C.B.Clish,J.A.O’Brien,M.W.Freeman和C.N.Serhan,1999,用白三烯B4受体转基因小鼠新发现了脂氧素和阿司匹林激发的脂氧素在再灌注中的保护作用,临床研究杂志,104:309-316)。已发现,COX的至少两种异构体,非甾体类消炎药(NSAIDs)的典型作用位点在人体中似乎具有不同的生理和病理作用(12.Herschman,H.R.,1998,***素合成的细胞与分子生物学的最新进展,心脏病医学动态,8:145-150)。每个COX异构体各自具有双加氧酶和过氧合酶两种酶活性。抑制COX-2是当前许多制药公司的研发重点,因为选择性地抑制COX-2而不抑制COX-1能够降低传统NSAID的不良副作用(13.Needleman,P.和P.C.Isakson,1997,COX-2的发现及其功能,类风湿学杂志,24(增刊49):6-8)。在这方面,用传统NSAID阿司匹林(ASA)对COX-2乙酰化可阻止***素类激素的形成,但乙酰化后的该酶仍能由C20:4原位产生15R-羟基二十碳四烯酸(15R-HETE),由活化炎性细胞释放并转化为15-差向异构体LX(14.Chiang,N.,T.Takano,C.B.Clish,N.A.Petasis,H.-H.Tai和C.N.Serhan,1998,阿司匹林触发的由人白细胞和鼠腹膜炎渗出物产生15-表-脂氧素(15-epi-lipoxin)A4ATL):一种特异性15-表-LXA4 ELISA,药物实验治疗学杂志,287:779-790和15.Xiao,G.,A.-L.Tsai,G.Palmer,W.C.Boyar,P.J.Marshall和R.J.Kulmacz,1997,关于过氧合氢诱导的经阿司匹林处理过的人***素H合成酶-2的酪氨酰基和脂氧合酶活性,生物化学,36:1836-1845-1845)。这些天然局部介体的合成类似物具有更长的生物学半衰期,表现出强抗炎性,表明:细胞-细胞相互作用能够通过调节对宿主防御机制具有重要意义的信号过程使AA(和/或其他脂质和PUFA,见图1)转化为抗炎性介体(参考文献11和16,Clish,C.B.,J.A.O’Brein,K.Gronert,G.L.Stahl,N.A.Petasis和C.N.Serhan,1999,稳定的阿司匹林触发的脂氧素的局部和全身性给药抑制体内嗜中性粒细胞的聚集,美国科学院院报,96:8347-8252)。
发明概述
阿司匹林能抑制***素的生物合成,但不直接作用于脂氧合酶,而是通过对环氧合酶2(COX-2)乙酰化形成碳15位上差向异构的生物活性脂氧素(LX)(15-表-LX,又称阿司匹林触发的LX[ATL])。本发明发现,经ω-3聚不饱和脂肪酸和阿司匹林(ASA)处理的小鼠的炎性渗出物可产生一系列新的生物活性脂质信号。ASA处理COX-2上调的人内皮细胞可将C20:5ω-3转化为18R-羟基二十碳五烯酸(HEPE)和15R-HEPE。两者都被多形核白细胞用来生成不同的三羟基类介体,其中包括5-系列的15R-LX和5,12,18R-LX-triHEPE。已证明,这些新的化合物在体内是人多形核白细胞经内皮迁移和浸润的强抑制剂(ATL类似物>5,12,18R-LX-triHEPE>18R-HEPE)。对乙酰氨基酚和吲哚美辛也能由重组COX-2以及ω-5和ω-9形成18R-HEPE和15R-HEPE,并能发生其他新的聚不饱和脂肪酸(例如C18:3,C22:6)的氧合,并作用于血管、脑、炎性细胞和血细胞。以上发现确立了产生生物活性脂质介体作用于微观炎性反应的的新的跨细胞路径:COX-2-非甾体消炎药-依赖性氧合作用和细胞-细胞相互作用。这些介体及相关化合物的产生为饮食补充ω-3的医疗效用提供了新的机制,这对于炎症、肿瘤和血管疾病具有重要意义。
内皮细胞(EC)内P450对C20:4的氧合作用也会最终形成抑制EC活化的11,12-环氧二十碳四烯酸,同时,EPA的非酶氧合则下调EC粘附分子(17.Node,K.,Y.Huo,X.Ruan,B.Yang,M.Spiecker,K.Ley,D.C.Zeldin和J.K.Liao,1999,细胞色素P450环氧合酶衍生的类花生酸的抗炎特性,科学,285:1276-1279和18.Sethi,S.,A.Y.Eastman和J.W.Eaton,1996,氧合脂肪酸对吞噬细胞-内皮细胞相互作用的抑制:一种天然抗炎机制?,实验室临床医学杂志,128:27-38)。PMN-血管相互作用对聚集和PNM-依赖性组织损伤至关重要,所以,参与它们“交叉对话”的局部信号具有重要意义。本发明发现,被阿司匹林乙酰化的COX-2仍具有产生特异性ATL的体内活性,ATL可以作为已知抗炎反应的效应剂,这些提供了ASA有益效果不仅缘于抑制***素类激素的机制(参考文献8,12,14)。ASA及相关NSAID的新治疗用途仍在不断涌现。但是,它们一般都要求分子水平的定义以形成理论。这包括报道的:ASA预防结肠直肠癌和降低二次心肌梗塞发生率的作用(19.Levy,G.N.,1997,***素H合成酶,非甾体类消炎药,和结肠癌,FASEB J.,11:234-247)。基于以上归于饮食ω-3 PUFA对人类疾病的相互交迭的有益作用(参考文献1-6),本发明是关于产生脂质信号的新路径,他们提供了以上有益作用的分子基础,也可作为其标记(marker)。
本发明涉及一种治疗或预防哺乳动物炎症的方法,即给予聚不饱和脂肪酸(PUFA)与阿司匹林的组合物,所述聚不饱和脂肪酸包括C18:3,C20:4和C22:6。实施方式之一中,ω脂肪酸,例如C18:3或C22:6,和阿司匹林分两个不同时刻给予。本发明还涉及治疗哺乳动物动脉炎、关节炎、牛皮癣、荨麻疹、脉管炎、哮喘、眼科炎症,肺炎、肺纤维变性、脂溢性皮炎、脓疱性皮肤病,或心血管疾病的方法,即给予ω-脂肪酸和阿司匹林的组合物。
另一实施方式中,本发明治疗或预防哺乳动物炎症的方法是给予以下结构式之一所示ASA-触发的天然脂质(ω-3)介体及其立体异构体,例如其对映体、非对映体或外消旋混合物:
或
其中,R是氢原子或构成它们的药用盐、酯、酰胺或前药,例如它们的药用类似物。优选的类似物。优选的类似物包括其甲酯、乙酯和甘油酯。P是H(羟基)或合适的保护基。所述羟基保护基包括:酯(乙酸酯,乙酸乙酯),醚(甲醚,***),乙氧基化衍生物(乙二醇,丙二醇)和硅烷化基团(TMS或TIPPS)。
另一实施方式中,本发明涉及用于治疗或预防哺乳动物炎症的组合物和方法,所述方法即给予ASA-触发的天然脂质(ω-2,ω-3或ω-4)介体类消炎药,即单羟基化的二十二碳六烯酸(DHA)(C22:6),又即:13-羟基-DHA,14-羟基-DHA,16-羟基-DHA,17-羟基-DHA,19-羟基-DHA或20-羟基-DHA,其中的羧酸可以是氢原子形式,或官能化为药用盐、酯、酰胺或前药,例如它们的药用类似物。优选的类似物包括其甲酯、乙酯和甘油酯。也可以将单羟基化DHA化合物的羟基保护起来。合适的保护基包括:酯(乙酸酯,乙酸乙酯),醚(甲醚,***),乙氧基化衍生物(乙二醇,丙二醇)和硅烷化基团(TMS或TIPPS)。
本发明内容之一中,本发明的化合物用已知方法基本纯化和分离。纯化产物的纯度一般至少约90%,至少约95%更好,至少99%最好。
另一实施方式中,本发明涉及治疗哺乳动物动脉炎、关节炎或心血管疾病的方法,该方法包括给予该哺乳动物一种或多种上述化合物。
出人意料的是,本发明发现:阿司匹林、COX-II与ω-3和ω-6脂肪酸之间的相互作用对组织具有消炎作用。而且,以上组合产生了独特的前文所示化合物。这些化合物具有抗炎性,并可用作消炎药治疗并发炎症的疾病或症状。
本发明化合物和方法的优点在于副作用极小。本发明化合物靶向于嗜中性粒细胞,因而避免了NSAID的常见副作用。NSAID具有广泛的生物学/生理学作用,而本发明化合物则具有更强的嗜中性粒细胞选择性。由于这些化合物是嗜中性粒细胞导向性消炎药,其副作用与常规NSAID相比显著降低。本发明化合物的诸如便秘、肾毒性和胃肠溃疡或出血等副作用极小。以上优点为患者缓解炎症提供了有效的选择,从而不必忍受NSAID的副作用。
附图说明
根据后文的详细描述并结合附图,可更好地理解本发明。
图1:脂质介体(LM)的跨细胞生物合成。
图2A:经环氧合酶2(COX-2)作用,由14C-标记的花生四烯酸(AA,ω-6)生成的产物的薄层层析。
图2B:经阿司匹林乙酰化COX-2作用,由14C-标记的花生四烯酸(AA,ω-6)生成的产物的薄层层析。
图2C:经环氧合酶II(COX-2)作用,由14C-标记的二十碳五烯酸(EPA,ω-3)生成的产物的薄层层析。
图2D:经阿司匹林乙酰化COX-2作用,由14C-标记的EPA(ω-3)生成的产物的薄层层析。
图3:巨大芽孢杆菌(B.Megaterium)转化EPA(ω-3)的LC/MS离子层析和质谱分析。
图4A:阿司匹林处理的小鼠背气囊(air-pouch)炎性渗出物中,由EPA生成的单羟基产物的LC/MS离子层析。
图4B:阿司匹林处理的小鼠背气囊炎性渗出物中,由EPA生成的18-HEPE的质谱分析。
图4C:阿司匹林处理的小鼠背气囊炎性渗出物中,由EPA生成的5S-HEPE的质谱分析。
图4D:阿司匹林处理的小鼠背气囊炎性渗出物中,由EPA生成的5,12,18R-triHEPE的质谱分析。
图5:经巨大芽孢杆菌作用,由5S,12R-二羟基-6Z,8E,14Z,17Z-二十碳五烯酸(ω-3)生成的5,12,18-triHEPE异构体的LC/MS离子层析。
图6:用肿瘤坏死因子(TNF-α)和阿司匹林处理的小鼠背气囊。
图7A:用阿司匹林和EPA处理的IL-1β-刺激的人脐带内皮细胞(HUVEC)产生的18R-HEPE的LC/MS离子层析。
图7B:阿司匹林乙酰化COX-2和血清处理的酵母聚糖(STZ)刺激的人PMN由EPA产生的triHEPE的LC/MS离子层析。
图7C:图7B中triHEPE的产物I:5,12,18R-triHEPE的质谱分析。
图7D:图7B中triHEPE的产物II:15-表-LXA5的质谱分析。
图8:经阿司匹林乙酰化COX-2作用由EPA生成的单羟基产物的选定离子监测所得LC/MS/MS层析,附带18-HEPE,15-HEPE和11-HEPE的质谱分析。
图9A:18R-HEPE(空心圆),5,12,18R-HEPE(实心圆)和一种阿司匹林触发的脂氧素(ATL)类似物(参照化合物)(实心方形)对LTB4激发的PMN经内皮细胞迁移的抑制作用。
图9B:18R-HEPE(空心圆),5,12,18R-HEPE(实心圆),LTB5(空心方形),或同源配体(homoligand)LTB4(实心方形)之间与HEK-293细胞稳定表达的重组人LTB4受体的竞争性结合。
图9C:静脉注射100ng 18R-HEPE,5,12,18R-HEPE或作为参照化合物的ATL类似物(用15(S)-16(对氟)-苯氧基-LXA4进行比较,N=4)后,TNF-α诱导的白细胞向小鼠背气囊内浸润受到的抑制。
图10A:由二同-γ-亚油酸(C20:3,ω-3)与阿司匹林乙酰化COX-2所得单羟基产物的LC/MS/MS离子层析和质谱分析。
图10B:由亚麻酸(C18:3,ω-3)与阿司匹林乙酰化COX-2所得单羟基产物的LC/MS/MS离子层析和质谱分析。
图10C:由亚油酸(C18:2,ω-6)与阿司匹林乙酰化COX-2所得单羟基产物的LC/MS/MS离子层析和质谱分析。
图11:由ω-3PUFA经跨细胞加工产生一系列功能性脂质信号过程的假设:微炎症的内源性抑制剂。在COX-2上调并以NSAID处理的部位,由C20:4形成***素被抑制。全身性的ω-3PUFA通过COX-2-NSAID脂氧合酶机制被转化为15R-H(p)EPE或18R-H(p)EPE:(分图A)由环氧合物在EPA(C20:5)的C16或C13位上立构特异性地夺取氢而引起分子氧的R型***,生成15R-H(p)EPE或18R-H(p)EPE;或者还原成醇;或类似地在DHA(C22:6)的C13或C17位***分子氧而生成13-羟基-DHA或17-羟基-DHA(分图B)。三羟基化合物的完整立体化学特征尚有待测定,所显示的是它们的可能性构型。这些化合物与局部微观环境中的细胞相互作用,抑制PMN的聚集。含有1,4-顺式戊二烯单元的ω-3 PUFA会发生COX-2-NSAID-依赖性夺氢和分子氧的***。
图12:产生新的脂质介体(同时也是阿司匹林处理的标记)的阿司匹林乙酰化COX-2依赖性路径。
图13:由二十二碳六烯酸(DHA,C22:6,ω-3)与阿司匹林乙酰化COX-2产生的主产物和次产物的结构。
图14A:由阿司匹林乙酰化COX-2触发的DHA产物曲线变化。左边的LC/MS离子层析显示:没有阿司匹林时,13-羟基-DHA是主产物。右边的显示:COX-2被阿司匹林乙酰化后,13-羟基-DHA的产生被抑制,17-羟基-DHA成为主产物。
图14B:DHA经阿司匹林乙酰化COX-2作用形成的13-羟基-DHA的LC/MS/MS离子层析和质谱分析。
图14C:DHA经阿司匹林乙酰化COX-2作用形成的14-羟基-DHA的LC/MS/MS离子层析和质谱分析。
图14D:DHA经阿司匹林乙酰化COX-2作用形成的16-羟基-DHA的LC/MS/MS离子层析和质谱分析。
图14E:DHA经阿司匹林乙酰化COX-2作用形成的17-羟基-DHA的LC/MS/MS离子层析和质谱分析。
图14F:DHA经阿司匹林乙酰化COX-2作用形成的19-羟基-DHA的LC/MS/MS离子层析和质谱分析。
图14G:DHA经阿司匹林乙酰化COX-2作用形成的20-羟基-DHA的LC/MS/MS离子层析和质谱分析。
图15:阿司匹林乙酰化-COX-2氧合反应在ω-3和ω-6 PUFA内的区域选择性。
本发明的详细说明
以下将更详细地说明本发明的特征及其他细节。必须认识到,具体实施方式仅是举例说明而非对本发明的限定。本发明的主要特征可运用于多种方式实施,这些都属于本发明范围之内。
简便起见,本文使用了以下缩略语:NSAID:非甾体类消炎药;PUFA,聚不饱和脂肪酸;ALXR,LXA4受体;ASA,阿司匹林;ATL,阿司匹林触发的15-表-LX,15R-LX;ATLM,阿司匹林触发的脂质介体;COX,环氧合酶I,II(异构体);EC,内皮细胞;HUVEC,人脐脉管内皮细胞;LC/MS/MS,液相层析串联质谱;LM,脂质衍生的介体;LO,脂氧合酶;LT,白三烯;LX,脂氧素;PG,***素;PMN,多形核白细胞;EPA,二十碳五烯酸;HEPE,羟基二十碳五烯酸;HETE:羟基二十碳四烯酸;LXA4,5S,6R,15S-三羟基-7,9,13-反式-11-顺式-二十碳四烯酸;15-表-LXA4,5S,6R,15R-三羟基-7,9,13-反式-11-顺式-二十碳四烯酸;C20:5(二十碳五烯酸,EPA,ω-3脂肪酸);C20:4(花生四烯酸,AA,ω-6脂肪酸);和C22:6(二十二碳六烯酸,DHA,ω-3脂肪酸)。
本发明涉及用ω-3脂肪酸与阿司匹林治疗或预防哺乳动物炎症的方法。实施方式之一中,EPA或DHA之类ω脂肪酸与阿司匹林分别在两个不同时刻给予。本发明还涉及使用EPA或DHA之类ω脂肪酸与阿司匹林的组合物治疗哺乳动物动脉炎、关节炎或心血管疾病的方法。
另一实施方式中,本发明是用以下结构之一所示消炎药治疗或预防哺乳动物炎症的组合物和方法。化合物1的结构式为:
优选实施方式之一中,C15位的羟基呈R构型。另一实施方式中,C15位的羟基呈S构型。或者,C15位上的羟基的R/S构型的外消旋混合物。
化合物2的结构为:
优选实施方式之一中,C18位的羟基呈R构型。另一实施方式中,C18位的羟基呈S构型。或者,C18位上的羟基的R/S构型的外消旋混合物。
化合物3的结构为:
优选实施方式之一中,C5位的羟基呈S构型,C6位的羟基呈R构型,C15位的羟基呈R构型。另一实施方式中,C5位的羟基呈R/S构型,C6位的羟基呈R/S构型,C15位的羟基呈R/S构型。
化合物4的结构为:
实施方式之一中,5-羟基呈S构型,12-羟基呈R构型,18-羟基呈R构型。另一实施方式中,5-羟基呈R/S构型,12-羟基呈R/S构型,18-羟基呈R/S构型。
化合物5的结构为:
将其命名为13-羟基-DHA,其中,P=H(羟基)。实施方式之一中,13-羟基呈S构型。另一实施方式中,13-羟基呈R构型。另一实施方式中,13-羟基是外消旋混合物,例如R/S构型。
化合物6的结构为:
将其命名为14-羟基-DHA,其中,P=H(羟基)。实施方式之一中,14-羟基呈S构型。另一实施方式中,14-羟基呈R构型。另一实施方式中,14-羟基是外消旋混合物,例如R/S构型。
化合物7的结构为:
将其命名为16-羟基-DHA,其中,P=H。实施方式之一中,16-羟基呈S构型。另一实施方式中,16-羟基呈R构型。另一实施方式中,16-羟基是外消旋混合物,例如R/S构型。
化合物8的结构为:
将其命名为17-羟基-DHA,其中,P=H。实施方式之一中,17-羟基呈S构型。另一实施方式中,17-羟基呈R构型。另一实施方式中,17-羟基是外消旋混合物,例如R/S构型。
化合物9的结构为:
将其命名为19-羟基-DHA,其中的P=H。实施方式之一中,19-羟基呈S构型。另一实施方式中,19-羟基呈R构型。另一实施方式中,19-羟基是外消旋混合物,例如R/S构型。
化合物10的结构为:
将其命名为20-羟基-DHA,其中,P=H。实施方式之一中,20-羟基呈S构型。另一实施方式中,20-羟基呈R构型。另一实施方式中,20-羟基是外消旋混合物,例如R/S构型。
化合物1至10中,R是氢原子或构成药用盐、酯(例如甲酯)、酰胺或前药。优选类似物包括甲酯、乙酯和甘油酯。
化合物1至10中,“羟基”的立体化学特征只是举例,它包括保护的羟基和游离羟基。
可用各种已知保护基来保护化合物1至10中的“羟基”,本领域技术人员不难确定用什么保护基来保护羟基。相关的标准方法是已知的,在文献中有详细的记载。例如,本领域技术人员可根据Green和Wuts在“有机合成中的保护基”,John Wiley andSons,第5章和第7章(1991)所述选择合适的保护基。优选的保护基包括:甲酯和乙酯,TMS或TIPPS基团,乙酸酯或丙酸酯基团,二醇醚,例如乙二醇和丙二醇衍生物。
例如,可用温和的碱例如三乙基胺在酰氯或硅烷氯存在下处理一个或多个羟基,促进羟基离子与卤化物间的反应。或者,卤代烷基可与羟基离子(由二异丙基酰胺锂之类碱产生)反应,促进醚形成。
必须明白,对化合物3和4而言,并非所有的羟基都需要保护,可以仅保护1、2或3个,这可以通过按照化学计量使用羟基保护剂来实现。可用已知方法来分离单保护、二保护或三保护羟基化合物,例如HPLC,LC,快速层析,凝胶渗透层析,结晶,过滤等。
必须明白,以上所述化合物具有一个或多个手性中心,本发明包括各化合物的所有立体化学形式,例如对映体、非对映体和外消旋混合物。
“药用盐、酯、酰胺和前药”在此指本发明化合物的如下羧酸盐、氨基酸加成盐、酯、酰胺和前药:医学界已确认可与患者组织接触,没有过度毒性、刺激、过敏反应等副作用,具有合理的效险比,并具有目标效用,还可能包括本发明化合物的两性离子形式。“盐”指本发明化合物的相对无毒的有机酸和无机酸加成盐。这些盐可在最后分离和纯化所述化合物时就地生成,也可以由纯化后的化合物以游离碱的形式另外与合适的有机酸或无机酸反应生成,然后分离纯化。所述盐包括碱金属和碱土金属阳离子盐,例如钠、锂、钾、钙、镁等,还包括无毒的铵、季铵和胺离子盐,所述胺离子包括但不限于铵,四甲基铵,四乙基铵,甲基铵,二乙基铵,三甲基铵,三乙基铵,乙基铵等。(可参考例如Berge S.M.等的“药用盐”,药物学杂志,1977;66:1-19)。
“前药”指在体内可迅速转化,例如在血液中通过水解,成为结构式所示亲本药的化合物。相关全面论述可参考T.Higuchi和V.Stella的“前药,一种新的给药***”,A.C.S.论丛Vol.14,和“药物设计中的生物可逆载体”,Edward B.Roche,AmericanPharmaceutical Association and Pergamon Press,1987。本发明中,作为前药的化合物使用后,在体内经代谢或其他途径转化为该化合物的生物学、药学或治疗学活性形式。为了形成前药,对药学活性化合物进行修饰,使其可经代谢过程而恢复活性。前药可用于改变药物的代谢稳定性或转运特征,掩蔽药物的副作用或毒性,改善药物的口感,以及其他特征。基于对药物动力学以及药物体内代谢的认识,一旦确定了一种药学活性药物,制药技术人员就能够设计出该化合物的前药(参考例如Nogrady(1985),药物化学,一种生物化学方法,Oxford University Press,New York,P.388-392)。选择和制备合适的前药衍生物的常规方法可参考例如“前药的设计”,H.Bundgaard,Elsevier,1985。前药的合适例子包括:适当酸的甲酯、乙酯和甘油酯。此外,只要能经代谢成为亲本化合物即恢复原羟基官能的羟基保护基都适合。
如本文所述,本发明化合物可配制成药物组合物。优选实施方式之一中,所述化合物可以缓释组合物的形式延长给药时间。缓释组合物是已知技术,本领域技术人员可根据常用参数配制出合适的组合物。最优实施方式中,可用本发明所述的甘油酯缓释组合物(例如透皮药贴)来治疗炎症。制备透皮药贴的合适方法可参考美国专利5,814,599,5,846,974或4,201,211。更具体地说,可用Ciba-Geigy Corporation和AlzaCorporation的贴类技术进行所述化合物的透皮给药。本发明药物组合物的给药可以是间歇,渐进,连续,以恒定或有控速度给予温血动物,例如人。此外,给药天数和每日给药次数是可调整的。较好的给药可使药物制剂中的活性成分对炎症产生作用。
另一实施方式中,本发明是治疗哺乳动物动脉炎、关节炎或心血管疾病的方法,该方法包括给与所述哺乳动物一种或多种所述化合物。
“对象”在此指各种受激发发生了炎性反应的活生物,包括但不限于:人、非人灵长类动物,例如猩猩及其他猿类和猴类;畜类,例如牛、绵羊、猪、山羊和马;宠物,例如狗和猫;实验动物(包括啮齿类),例如小鼠、大鼠和豚鼠等。对于“对象”的年龄和性别没有限制,因此包括了成年和新生的对象,以及胚胎,不论雄性还是雌性。
“哺乳动物”在此指能对抗原产生免疫反应的活生物,这包括但不限于非人灵长类动物,例如猩猩及其他猿类和猴类;绵羊、猪、山羊、马、狗、猫、小鼠、大鼠和豚鼠等。
本发明的药物组合物包含“治疗有效量”或“预防有效量”的本发明消炎药。“治疗有效量”指该量以一定的剂型在必要的时间内足以获得所需的治疗效果,例如消除或预防与各种疾病或情况相关的炎症。消炎药的治疗有效量取决于多种因素,例如疾病情况,年龄,性别,患者体重,该消炎药在各患者体内激发所需反应的能力。而且,在治疗有效量,抗体或抗体部分的所有毒性或不良作用都可被有益的治疗效果所抵消。“预防有效量”指该量以一定的剂型在必要的时间内足以获得所需的预防效果。通常,由于预防是在疾病发生之前或在其早期阶段,预防有效量低于治疗有效量。
可通过调整给药分案来获取最佳反应(例如治疗性或预防性反应)。例如,可根据治疗的迫切程度,一次性药团给药,一段时间内分次给药,或者成比例地减量或增量。特别好的是剂型单元形式的非肠胃给药组合物,所述剂型单元形式便于给药和保持剂型的一致性。剂型单元在此指适合哺乳动物患者一次使用的物理上独立的单元;各单元包含算得的可产生所需疗效的一定量的活性化合物和必需的药用载体。本发明所述的剂型单元直接取决于:(a)活性化合物的特性和具体的治疗效果和预防效果;和(b)制备活性化合物用于治疗患者过敏的故有限制。
本发明消炎药的治疗或预防有效量例如但不限于0.1-20mg/kg,以1-10mg/kg为佳。需要指出的是,剂量可因病情的严重程度而进行调整。而且,对任何一个具体对象而言,在整个疗程中都需要根据个体的特殊需要和医生的判断调整剂量,以上所述的剂量只是举例,而非限定。
本发明所述的消炎药,如化合物1-10可配制成合适的药物组合物来给药。所述药物组合物一般包含本发明的消炎药和药用载体。本文中的“药用载体”包括各种生理相容性的溶剂,分散介质,包衣剂,抗细菌和真菌剂,等渗调节剂和吸收阻滞剂等,例如:水、生理盐水,磷酸缓冲液,葡萄糖,甘油,乙醇等,以及它们的混合物。很多情况下,组合物中最好包括等渗调节剂,例如糖,甘露醇、山梨醇等多元醇,或氯化钠。药用载体还可以包括少量助剂,例如润湿剂,乳化剂,防腐剂或缓冲剂,这些能延长消炎药的保存期,增强其效力。
可将本发明的消炎药配制成非肠胃给药的药物组合物。其他合适的缓冲盐包括但不限于:琥珀酸钠,柠檬酸钠,磷酸钠和磷酸钾。可用0-300mM(对于液体剂型最合适的是150mM)氯化钠来降低溶液的毒性。冻干制剂中可包含防冻剂,一般为0-10%(0.5-1.0%更好)蔗糖,还包括海藻糖和乳糖。冻干剂中还可以包含填充剂,一般为1-10%甘露醇(2-4%更好)。液剂和冻干剂中都可以加入稳定剂,一般为1-50mM(5-10mM更好)L-甲硫氨酸。合适的填充剂还包括甘油、精氨酸,例如0-0.05%(0.005-0.01%更好)多乙氧基醚-80。表面活性剂还包括但不限于多乙氧基醚-20和BRIJ表面活性剂。
本发明组合物可以呈液体、半固体和固体剂型等各种形式,例如:液体溶液(注射和输注溶液),分散剂或悬浮剂,片剂,颗粒剂,粉末剂,脂质体和栓剂。优选剂型取决于给药方式和治疗目的。典型的优选组合物形式是注射或输注溶液,例如类似于被动免疫时所用的组合物。优选的给药方式是肠胃外给药(例如静脉、皮下、腹膜内、肌内给药)。优选实施方式之一通过静脉输液或注射给予所述消炎药。另一优选实施方式通过肌内或皮下注射给予所述消炎药。最好的是口服给予所述消炎药。
治疗用组合物必须无菌并在制造和保存条件下保持稳定。可将组合物配制成溶液、微乳液、分散剂、脂质体或其他规则结构以配合药物的高浓度。无菌注射溶液的制备可以是:将所需量的活性化合物(例如抗原,抗体或抗体片段)与所需的一种或多种上述成分一同加入合适的溶剂,然后过滤除菌。
分散系一般是将活性化合物加入无菌载体中制备而成,所述载体包含主要的分散介质和所需的其他成分,例如前文所述。如果是无菌注射溶液的无菌冻干粉末,优选的制备方法是:将活性成分与所需的附加成分制备成溶液,除菌过滤后,通过真空干燥和喷雾干燥得到粉剂。保持溶液适当的流动性可以采用卵磷脂包衣,保持分散剂中颗粒大小适当,以及采用表面活性剂。延迟注射组合物的吸收可以通过在组合物中加入吸收阻滞剂,例如单硬脂酸盐和明胶。
本发明的消炎药可以本领域已知的多种方式给药。本领域技术人员知道,给药方式或途径取决于所需的效果。某些实施方式中,可将活性化合物包含在载体内,该载体可保护该化合物不至于立即释放,例如植入体、透皮药贴和微胶囊给药***等缓释剂型。可以采用可生物降解的、生物相容性聚合物,例如乙烯乙酸乙烯酯,聚酐,聚乙醇酸,胶原,聚原酸酯和聚乳酸。许多制备此类制剂的方法是专利技术或本领域的已知技术。例如,缓释和控释给药***,J.R.Robinson编,Marcel Dekker,Inc.,NewYork,1978。
某些实施方式中,本发明的消炎药可与惰性稀释剂或可吸收的可食载体一同口服。也可以将所述化合物(以及需要的其他成分)装入硬胶囊或软胶囊,或压成片剂,或直接加入食物。就口服治疗而言,所述化合物可与赋形剂混合,以吞咽片剂、含片、锭剂、胶囊、酏剂、悬浮剂、糖浆、薄片剂等形式使用。为了通过非肠胃给药之外的方式使用本发明的化合物,可能有必要对所述化合物进行包衣,或同时给予其他物质,以防其失活。
如前所述,本发明的化合物1-10及其药用类似物可用于预防或治疗与致炎性COX酶相关的临床症状。例如,本发明的化合物能与COX酶相互作用,从而可预防和治疗与痉挛、变应反应、血小板凝集以及普通炎症等相关的炎性病症。
致痉性病症包括平滑肌痉挛,尤其是气道平滑肌收缩和动脉平滑肌收缩,前者例如哮喘(包括原发性支气管哮喘),支气管炎,后者例如冠状动脉痉挛(包括与心肌梗塞相关的冠状动脉痉挛,这可能但不一定引起左心室衰竭,继而导致心源性哮喘),缺血性心肌损伤和脑痉挛或中风(可能导致中枢神经病变)。还包括结肠肌异常收缩引起的肠道疾病,例如肠炎、结肠痉挛和粘液性结肠炎。
变应性病症的例子包括外源性哮喘,局部或全身性皮肤过敏(例如湿疹),过敏性肠病(包括腹腔疾病),过敏性眼病,例如枯草热(可能影响上呼吸道),过敏性鼻咽和过敏性结膜炎。
血小板凝集相关性病症的例子包括血栓引起的病症,例如全身性或局部血栓引起的中风,冠状动脉血栓,静脉炎和静脉血栓形成(后两种情况也可能与炎症有关)。
炎性病症的例子包括肺、关节、眼、肠、皮肤和心脏等器官的炎症;尤其是与白细胞浸润进入发炎组织相关的炎症。肺部炎性病症包括哮喘,成人呼吸窘迫综合征,支气管炎和囊性纤维变性(这还可能影响到肠或其他组织)。炎性关节疾病包括类风湿关节炎,类风湿脊椎炎,骨关节炎,痛风性关节炎和其他关节炎类病症。炎性眼病包括葡萄膜炎(包括虹膜炎)和结膜炎。炎性肠病包括Crohn′s病,溃疡性结肠炎和末端直肠炎。
炎性皮肤病包括与细胞增殖相关的皮肤病,例如牛皮癣,湿疹,皮炎,包括湿疹性皮炎,例如特应性皮炎和脂溢性皮炎,过敏性或刺激性接触性皮炎,干性湿疹,光敏性皮炎,光毒性皮炎,植物性光毒性皮炎,放射性皮炎和停滞性皮炎。炎性皮肤病还包括但不限于:创伤、烧伤、大疱性疾病或皮肤或粘膜缺血引起的溃疡和糜烂;多种形式的鱼鳞癣;大疱性表皮松解;肥厚性瘢痕和瘢痕瘤;内源性老化和光老化引起的皮肤变化;机械摩擦引起的水疱;局部使用皮质类固醇引起的皮肤萎缩。此外,炎性皮肤病还包括粘膜炎症,例如唇炎,唇皲裂,鼻刺激和外阴***炎。
炎性心脏疾病的例子包括冠状动脉梗死性损伤。其他炎性疾病包括慢性炎症中的组织坏死,内毒性休克,平滑肌增生性疾病(例如血管再造术后的再狭窄)和移植手术后的组织排斥。
此外,还包括其他炎性疾病。所有表现出炎症状态或本发明所述各种症状的疾病都包括在本发明所述“治疗炎症”的概念之中。此外,以上列举的炎性疾病只是举例而非限定。本领域技术人员可以看出还有其他炎性病症也符合减轻炎症的概念,其中,因损伤或刺激,对象的局部PMN和/或白细胞水平高于正常状态。
因此,本发明提供了一种预防或治疗痉挛、变应反应、血小板凝集或炎症相关性临床病症的方法。所述治疗方法包括给予治疗有效量的一种或多种本发明化合物1-10或其药用类似物。本发明还提供了一种预防或治疗HIV感染相关性神经变性或痴呆的方法,包括给予治疗有效量的一种或多种本发明化合物1-10或其药用类似物。
实施方式之一,可将本发明的消炎药加入用于清洁头皮和/或身体的香波或身体清洁产品(例如肥皂)。这可以用于治疗牛皮癣,脂溢性皮炎,脓疱性皮肤病和头屑。此外,还可以将本发明的消炎药如化合物1-10加入局部用的洗液,用于治疗上述疾病和晒伤、毒漆藤皮炎,和用于延缓迁移性癌症的发展。或者,可用本发明化合物治疗Alzheimer病,因为已知消炎作用有助于降低长期成斑效应。另一实施方式中,可以气溶胶或喷雾剂的形式用本发明化合物治疗气道炎症,例如支气管炎,哮喘,肺炎,肺气肿或上呼吸道疾病。
可在组合物中加入增效性活性化合物。某些实施方式中,本发明的消炎药与一种或多种治疗炎症损伤性疾病的其他治疗剂制成合剂和/或一同给药。例如,可将本发明消炎药与一种或多种结合其他目标如受体的其他消炎化合物制成合剂和/或一同给药。此外,可将本发明的一种或多种消炎药与两种或更多所述治疗剂联用。这样的联合治疗可更好地利用所给药物剂量较低来避免各种药物单用疗法中可能发生的毒性或并发症。
出人意料的是,本发明发现阿司匹林、COX-II和ω-3脂肪酸之间的相互作用对组织具有消炎作用。而且,这样的联合产生了独特的前文结构式所示化合物。这些化合物具有消炎作用,可用作消炎药来治疗炎症相关性病症。
两类类花生酸,即LT和PG,可介导与人类疾病相关的重要效应。虽然已知LT和PG具有促炎作用(见图1),本发明的新证据表明:新发现的LM及其稳定类似物在PMN性组织损伤和急性炎症中具有强效反调节作用。在这方面,已知花生四烯酸在内皮细胞(EC)内可经p450作用氧合形成11,12-EET,它具有消炎作用,能抑制白细胞粘附分子,EPA非酶氧合也能产生下调EC的产物,但尚未鉴定。
目前发现:宿主的总体反应,即已知人类疾病例如动脉炎、关节炎、心血管病、老年性炎性疾病、刺激性肠(结肠)病、丹毒、湿疹、牛皮癣、荨麻疹、脉管炎、AIDS相关性炎症、眼睛炎症、哮喘、肺炎、肺纤维变性,一定程度上反映了炎性信号利弊之间的总体平衡。此类信号中,LM的作用尚未确定,可能是因为它们通过跨细胞生物合成产生的速度快,寿命短,而且限于局部作用。因此,由花生四烯酸及其代谢稳定性类似物形成的脂氧素(LX)和最近阐明的阿司匹林触发的LX(ATL)已开始受到关注,因为它们较长的生物半衰期增强了它们在体内的有益作用。
鉴于ASA可触发形成天然生物活性类花生酸的差向异构体(参考文献9),所以对NSAID能否促进由ω-3PUFA形成新的介体进行了试验。给小鼠囊内注射TNF-α与ω-3和ASA(2h),小鼠气囊内的炎性渗出物包含了产生的几种新化合物(图4)。给这些小鼠喂以含0.26%ω-3PUFA的标准鼠食。对由渗出物所得物质的LC/MS/MS分析显示,在m/z317响应的选定离子层析(图4A)中显示为单羟基酸,即18-羟基-EPA(18-HEPE)和5-HEPE,它们与合成的5S-HEPE和由C20:5形成的新的三羟基化合物共洗脱。LC停留时间和MS/MS质谱(图4B和4C)显示的产物离子与所示结构相符,即m/z 317=(M-H)~-H2O-CO2。与18-HEPE相符的诊断离子出现于m/z 259(图4B)显示,与5-HEPE相符的出现于m/z 115(图4C)。以下一律用这些标准进行鉴定。用手性层析柱确定由渗出物所得18-HEPE内C18上羟基的立体化学特征,同时,由巨大芽孢杆菌生物合成18R-HEPE作为参照物(见图5,材料与方法)。该微生物能使脂肪酸一氧合,(例如)可将C20:4转化为18R-HETE(22.Capdevila,J.H.,S.Wei,C.Helvig,J.R.Falck,Y.Belosludtsev,G.Truan,S.E.Graham-Lorence和J.A.Peterson。1996。细胞色素P450BM-3对聚不饱和脂肪酸的高度立体选择性氧合,生物化学杂志,271:22663-22671;和23.Ruettinger,R.T.,和A.J.Fulco,1981,巨大芽孢杆菌的可溶性细胞色素P-450依赖性***的不饱和脂肪酸一氧合作用,生物活性,256:5728-5734)。第18位上羟基的构型被证明为>98%R。以上结果表明,鼠炎性渗出物体外接触C20:5,ω-3和ASA可产生5-脂氧合酶路径5-系列5S-HEPE,用人PMN也可鉴定到该化合物,还产生一种新的18R-HEPE,对其形成途径进行了测定(见后文)(24.Lee,T.H.,J.M.Menica-Huerta,C.Shih,E.J.Corey,R.A.Lewis和K.F.Austen,1984。二十碳五烯酸的5,12-二羟基衍生物,包括白三烯B5和双脂氧合酶产物的鉴定和生物特性。生物化学杂志,259:2383-2389)。以上经ASA和EPA处理的小鼠的气囊炎性渗出物细胞中主要是PMN(见图4),比单用TNF-α处理所得渗出物中少25-50%(n=3,图6)。此外,当这些渗出物以离子载体A23187(4μM)激活时,产生基本等量的18R-HEPE(10.2±4.3ng/104细胞)和5S-HEPE(10.9±2.9ng/104细胞)。图4A-D为LC/MS/MS,显示经阿司匹林处理后鼠背气囊炎性渗出物产生了新的化合物;第6小时收集FVB小鼠接受ASA(第3.5小时,500μg/个气囊)和EPA(第4小时,300μg/个气囊)后的TNF-α诱导的白细胞渗出物,结果每个气囊含2.3±0.5×106白细胞(见“方法”部分);
这些炎性渗出物还证明产生了新的三羟基化合物(图4D)。MS/MS中显示的离子与一种由20∶5所得的三羟基化合物一致,即,m/z亲本离子出现于349=(M-H)-,具有明显结构特征的产物离子出现于m/z 291和195,这符合对所***结构式的分解(图4D)。此外,可观察到一个共轭三烯特征性的270nm处最大UV吸收,连同m/z 291时的响应(剪切位置在C17-C18)和20碳的结构,表明18R-HEPE和triHEPE在生物合成上是相互关联的。
确定人细胞是否也能产生这些新的化合物以及它们是否具有生物活性十分重要。为此,用EPA脉冲处理并用ASA处理人EC,已知该细胞可因IL-1β或缺氧而诱导COX-2,然后对渗出物进行LC/MS/MS分析(图7A)。m/z 259的选定离子监测显示:ASA处理的HUVEC将EPA转化为18R-HEPE(图7A)。此外,ASA和EPA处理的HUVEC产生18-HEPE(10.6ng/104细胞)和15-HEPE(6.0ng/106细胞)(n=2,4次测定,数据未显示)。以上结果提示COX-2参与了以上化合物的产生,并用重组人COX-2接触ASA和ω-3PUFA得到了印证(图8和表1),以上发现具有重要的临床意义。
如表1所示,亚油酸(C18:2)可转化成13-羟基-9Z,11E-十八二烯酸(13-HODE;n-5氧合)和9-HODE(ω-9),ASA可显著减少但非完全抑制它们的产生。AA可转化成15R-HETE(n-5)和11R-HETE(n-9),这与先前的发现相符。ASA通过乙酰化COX-2(参考文献9,14,15)触发其脂氧合酶活性,从而转向15R-HETE生产,但似乎不影响11R-HETE的形成(表1和图8)。11R-HEPE是EPA与COX-2反应的主产物,15R-HEPE(n-5)和18R-HEPE(n-2)则较少。用1-14C标记的EPA确认前体-产物关系(n=3,见图2和“方法”)。COX-2的ASA乙酰化(图8:各种新反应产物的质谱鉴定)使18R-HEPE(n-2)产量提高了约2倍,11R-HEPE则减少了85%以上(C20:5内的位置性氧合之比为1∶1∶0.3,即18R~15R>11R)。因此,综合以上结果表明:EC内COX-2的乙酰化是产生18R-HEPE和15R-HEPE的主要原因。
有趣的是,不同于分离的COX-2产物情况,11R-HEPE(自C20:5产生)和11R-HETE(自C20:4产生)都不是脉管EC的主产物(见表1和图7)。用选择性COX-2抑制剂NS398抑制以上两种氧合反应,结果似乎只有自EPA形成18R-HEPE未被抑制(表1)。以上结果提示:联用ASA和ω-3PUFA(即EPA,C20:5,ω-3)处理炎症(例如胞嘧啶引起的急性炎症)部位(图4,图6)可由COX-2将EPA转化为18R-HEPE和15R-HEPE。
因为人PMN可将ASA触发的、COX-2产生的15R-HETE转化为15-表-LXA4(参考文献9),而且人白细胞和鲑鱼巨噬细胞(26.Hill,D.J.,D.H.Griffiths和A.F.Rowley,1999,鲑鱼血小板具有12脂氧合酶活性但没有15脂氧合酶活性,生物活性和生物物理学学报,1437:63-70)可将EPA转化为5-系列LX(25.Serhan,C.N.,P.Y.Wong和B.Samuelsson,1987。自花生四烯酸和二十碳五烯酸形成的脂氧素及其相关化合物的命名。***素,34:201-204),所以,对参与吞噬乙酰化COX-2产生的C20:5、ω-3产物18R-HEPE和15R-HEPE的活化人PMN进行了评价。根据m/z349.5(M-H)-的选定离子监测分析所示化合物的基峰分子离子,血清处理的酵母聚糖(STZ),一种巨噬细胞刺激剂,显示乙酰化COX-2产生的C20:5产物被转化两类三羟基EPE(图7B)。图7C显示,其中之一的MS/MS与鼠细胞产物的(图4D)相同,并符合于m/z305,233,195和291处显示诊断离子(图4D)的5,12,18R-triHEPE的结构(图7C)。
该产物是一个带有18R-羟基的“LTB5-样”结构(见图7D,插图)。事实上,当用分离的18R-HEPE培养活化PMN时,它被转化为包括该产物在内的数种化合物。此外,与巨大芽孢杆菌和NADPH在pH8下(促进羟基化,参考文献23)一同培养的合成LTB5被转化为一种三羟基产物(n=3),具有m/z 291处的特征性18R羟基(图5),和用人PMN所得的结果相同(图7C)。以上彼此独立的证据表明:PMN吸收18R-HEPE,后者被其5-脂氧合酶转化,***分子氧,然后转化为5-过氧羟基-18R-DiH(p)EPE,再由5(6)环氧合物形成5,12,18R-triHEPE(一种18R型LTB5样产物),该产物可能具有LTB5的立体化学特征,并保留了前体的18R手性特征。
在一种类似的生物合成模式中,PMN通过5-脂氧合将15R-HEPE转化成一种5-系列LXA5类似物(图7D),也保留了此类物质的C15构型。其MS/MS谱显示主离子出现于m/z305,233和251,该物质是15-表-LXA5,与鲑鱼巨噬细胞内内源性EPA源的15S型LX5结构(5-系列)一致。此处,人PMN保留了前体的15R手性特征以形成15-表-LXA5(图7D),这是15-表-LXA4的一种5-系列ω-3类似物。与LX的生物合成一样,活化PMN对18R-和15R-HEPE的5-脂氧合转化都伴随着LTB4形成的减少(未显示)。综合以上结果显示,分离的人EC和PMN可由炎性渗出物产生新的化合物(图1-4,表1和2)。
经内皮迁移是PMN聚集和炎症中的关键,而且是公认的传统消炎治疗的作用目标(27.Cronstein,B.N.,S.C.Kimmel,R.I.Levin,F.Martiniuk和G.Weissmann,1992,皮质类固醇消炎作用的机制:糖皮质素受体调节白细胞与内皮细胞的粘附和内皮-白细胞粘附分子1与细胞内粘附分子1的表达,美国科学院院报,89:9991-9995)。能够调节上述细胞-细胞相互作用的内源性脂质介体意义重大。因此,对5,12,18R-triHEPE及其前体18R-HEPE对于人PMN迁移的作用进行了评价。这两种化合物都抑制LTB4激发的PMN经内皮迁移(图9A),5,12,18R-triHEPE的表观IC50是5-50nM,18R-HEPE的IC50>1.0μM。因此,新的5-系列化合物18R三羟基HEPE和18R-HEPE与15-表-LXA4及其ω物和类似物(为进行直接比较而进行了平行实验)一样抑制PMN迁移(图10A,表1和2)。它们的效力排序为:15-表-LXA4稳定类似物>5,12,18R-triHEPE>18R-HEPE。
已鉴定到了LTB4的G蛋白偶联受体(28.Yokomizo,T.,T.Izumi,K.Chang,T.Takuwa和T.Shimizu,1997,一种介导趋化性的白三烯B4的G蛋白偶联受体,自然,387:620-624)。为了确定18R型产物是否与人LTB4受体作用而抑制PMN,根据已知序列克隆并在HEK293细胞内稳定表达该受体(参考文献11),用其进行竞争性结合实验(图18B)。同源配体LTB4有竞争性,IC50约为2.5nM,18R-HEPE没有竞争性,LTB5和5,12,18R-triHEPE有竞争性,IC50约为0.5μM,趋势为:LTB5>5,12,18R-triHEPE。
虽然5,12,18R-triHEPE及其相关结构(即LTB5)的效力远低于4-系列LTB4,这与LTB5降低PMN活性相符(参考文献24),但它们取代[3H]LTB4的能力与当前已有的LTB4受体合成拮抗剂相当(数据未显示)。以上发现提示:如果能产量充足,5,12,18R-triHEPE可作为体内LT介导性反应的抑制剂,并可作为新受体拮抗剂合成的生物模板。
在以低剂量(100ng)尾静脉给药时,5,12,18R-triHEPE是PMN向鼠背气囊浸润的强抑制剂(图10C),相当于等剂量的15-表-LX稳定类似物(用于直接比较)。18R-HEPE还具有体内活性(<5,12,18R-triHEPE),但其对于分离的人PMN经内皮迁移的作用小得多,而且在上述浓度时与重组LTB4没有相互作用。
如表1所示,另用其他常用NSAID(即对乙酰氨基酚和吲哚美辛)与重组COX-2和C20:5组合进行试验(表2),确定它们是否改变向HEPE的转化。它们都抑制11-HEPE的形成,抑制率>95%。有趣的是,浓度高达2mM的对乙酰氨基酚或吲哚美辛存在下,仍有18R-HEPE和15R-HEPE的形成(约1∶1),虽然它们的水平比没有抑制剂时下降了3-8倍(n=3)。以上结果表明:并非只有ASA处理和花生四烯酸会发生ω-3脂肪酸氧合成R-单过氧羟基产物。事实上,C18:2,C18:3和C22:6也会被NSAID-COX-2复合物转化为新的产物(见图11A,B和C)。因此,这些常用NSAID和选择性COX-2抑制剂(表1和表2)仍允许通过活化EC与NSAID接触发生PUFA的氧合,其中,COX-2与所述药物的作用程度可产生PUFA新的氧合形式。
除了关于ω-3PUFA(即C20:5)可能对人类有益的报道(参考文献1-6)之外,迄今还没有关于人体内或分离细胞内COX-2氧合产生新生物活性化合物的论述。在鱼体内,C20:5和C20:4在巨噬细胞和血小板内代谢产生5-系列和4-系列的类花生酸,包括PG、LT和LX,丰度基本相同(参考文献26)。本发明认为:经ASA和EPA处理的小鼠的炎性渗出物产生了新的化合物(图4),这些化合物也可由人EC,重组COX-2和PMN产生(图5)。基于以毫克至克计的饮食补充ω-3PUFA(参考文献1-6)和可携带上调COX-2的微脉管***的大面积,以上实验(图4-8)表现出的EC及相邻细胞的EPA转化实际代表了该转化在局部微环境中的大量发生。当NSAID发挥治疗作用,即在微炎症中,发炎或病患组织中的这种COX-2-NSAID依赖性ω-3PUFA转化很可能被增强,此时,COX-2被上调,成为影响脂肪酸代谢的决定因素。
与15-表-LX的生物合成类似,EPA与COX-2产生的15R-HEPE在白细胞内经5-脂氧合反应形成5(6)-环氧合物,继而转化成15-表-LX5系列化合物(图11)。15-表-LX4的这些稳定类似物在其15-20位上被大基团修饰,可耐受灭活性酶的作用,且体内效力更强,可抑制PMN的迁移和主要促炎性细胞因子的产生和作用(参考文献10和16)。因此,5-系列15-表-LX的作用方式应彼此类似,因为它们都具有17-18双键,因而具有ω-3产生的15-表-LX类似物的作用。
因为COX-2-NSAID依赖性氧合(例如18R和15R)在体内产生了可抑制PMN经内皮迁移和浸润的生物活性化合物,这些为新的NSAID作用机制以及ω-3饮食补充提供了支持,即产生内源性功能性脂质信号物系列(表1和图4,图7),这些系列能够通过抑制微炎症中的关键反应而介导ω-3对人治疗实验中的有益作用。在这方面,COX-2还产生了下调血小板-EC相互作用的脂氧合酶产物13-HODE(表1和2)(29.Buchanan,M.R.,P.Horsewood和S.J.Brister,1998,12-和15-脂氧合酶单羟基化合物,12-和15-HETE和13-HODE对内皮细胞和血小板受体-配体结合反应的调节,***素与白细胞与必需脂肪酸,58:339-346),该产物和DHA(C22:6)(图10)一样包括在该路径系列和介体类别中(图12)。DHA还可被转化为新的反应产物(图13)。此外,ASA处理COX-2产生了不同的C17产物与C13产物之比(图14B-G)。这些新的COX-2产物可能在COX-2和DHA水平升高的脑血管***中发挥作用。因此,这些化合物可用于治疗神经组织炎症(例如Parkinson′s病,Alzheimer′s病等)。因此,本发明出人意料地发现,COX-2与NSAIDS的相互作用引起了大量脂质前体新的氧合作用,从而产生具有治疗用途的生物活性化合物(图15)。
目前认为,不良炎性反应会造成心血管疾病(Ridker,P.M.,M.Cushman,M.J.Stampfer,R.P.Tracy和C.H.Hennekens,1997,炎症、阿司匹林与看似健康的人的心血管疾病,新英格兰医学杂质,336:973-979)和PMN介导的组织损伤为主的临床综合征(参考文献11),这些细胞-细胞相互作用激发的新ω-3 PUFA加工路径以及NSAID新作用的发现为采用补充ω-3 PUFA来提供临床保护和形成控制微炎症的强效内源性介导机制开辟了新路(图4-1)。而且,本发明还为避免当前消炎治疗的不良副作用,以及制订有效食物补充ω-3的生化指数和/或指标提供了基础。
表1:PUFA和重组人COX-2与ASA或选择性COX-2抑制剂产生的羟基化合物
表2:NSAID-人重组COX-2(n-3C20:5的转化)
NSAID | 18R-HEPE | 15R-HEPE | 11R-HEPE |
ASA | 12.2±4.6 | 8.0±5.6 | 5.5±2.3 |
吲哚美辛 | 3.0±1.4 | 2.6±1.4 | 3.3±1.8 |
对乙酰氨基酚 | 5.5±2.4 | 4.6±1.2 | 6.7±3.0 |
仅COX-2 | 18.3±11.2 | 42.0±23.8 | 90±43.0 |
以上数值为平均值(ng)±SEM,n=3
实验
材料和方法
酵母聚糖,羟高铁血红素,NADPH和ASA购自Sigma-Aldrich。用于鉴定的EPA(Cayman Chemical)和其他合成标准物,羟基脂肪酸和中间体购自Cascade BiochemLtd.。巨大芽孢杆菌获自美国典型培养物保藏中心。用于液相层析随机质谱(LC/MS/MS)的材料由文献记载中的供应者提供(20.Gronert,K.,C.B.Clish,M.Romano和C.N.Serhan,1999,类花生酸生物合成的跨细胞调节,类花生酸学会,E.A.Lianos编,Humman Press,Totowa,NJ 119-144)。
人PMN用Ficoll梯度法新鲜分离自健康志愿者(不包括此前2周内服用过药物的人;Brigham and Women′s Hospital的方法No.88-02642)的静脉血,并进行计数。为了研究经内皮迁移(参考文献10),培养人脐静脉或微血管的EC(分别为HUVEC或HMVEC),在聚碳酸酯透性载体上先涂以0.1%明胶,然后接种HMVEC单层(传代1次,2次或3次),密度约2×105细胞/cm2,用于与NSAID和PUFA共培养。
在6-8周龄的雄性FVB小鼠(喂以含0.26%ω-3脂肪酸的标准鼠食)囊内(6d背气囊)注射TNF-α(R&D System)(参考文献16)以引发炎性渗出物,然后在第3.5小时注射ASA(500μg),第4小时注射C20:5(300μg/囊)。第6小时,进行囊内灌注(3ml生理盐水),计点渗出细胞数,并用94μM A23187激活(37℃,20min)。尾静脉注射18R-羟基二十碳五烯酸(HEPE),5,12,18R-HEPE或15-表-LXA,在第4小时进行囊内灌注,测定TNF-α激发的(100ng/囊,FVB小鼠)PMN浸润的受抑制情况。
用人LTB4受体稳定转染的人胎肾(HEK)293细胞进行[3H]LTB4(NEN Life ScienceProduct)比结合(Chiang,N.,K.Groner,C.B.Clish,J.A.O′Brien,M.W.Freeman和C.N.Serban,1999,白三烯B4受体转基因小鼠揭示了Lipoxius和阿司匹林触发的脂氧素在再灌注中新的保护作用,临床研究杂志,104:309-316)。将昆虫细胞(美国典型培养物保藏中心)培养物微粒体(约8μl)悬浮于Tris(100mM,pH8.0),5/9的细胞过量表达人重组COX-2(Dr.R.A.Copeland提供,DuPont Merck,Wilmington,DE)(参考文献21.George,H.J.,D.E.Van Dyk,R.A.Straney,J.M.Trzaskos和R.A.Copeland,1996,杆状病毒感染的昆虫细胞的重组人诱导型***素G/H合成酶的表达、纯化和鉴定,蛋白质表达与纯化,7:19-26)。在37℃加入NSAID(即约1mM的ASA),培养30分钟后加入PUFA(20μM),用1-14C-标记的C20:4(图2A和2B)或C20:5(NEN Life ScienceProduct)(图2C和2D)监测转化情况。
30℃,在Bacto营养培养液(Fisher Scientific)中振荡培养巨大芽孢杆菌,生物合成中间体和参照化合物。用生物合成法制备18R-HEPE的标准物,即巨大芽孢杆菌超声裂解物与NADPH(2mM)和C20:5(EPA)(330μM)在2M Tris缓冲盐(pH8.1)中共培养。用同样的条件将LTB5(15μM)转化为新的化合物;见结果。萃取培养物,以氚标记的内标(15-HETE和C20:4)进行LC/MS/MS分析,用的是配制有LUNA C18-2柱(150×2mm,5μM)和快速UV/Vis波谱扫描检测仪的Finnigan LCQ。用Chiralcel CB-H柱(J.T.Baker),恒溶剂洗脱法(己烷/异丙醇=96∶4(vol/vol)),测定单羟基-PUFA的羟基是R还是S构型。有关脂质介体分离、纯化和结构鉴定的详细方法可参考最近的文献报道,本发明即据此阐明本发明新的产物。
羟基-HAD化合物的制备:
分别用阿司匹林乙酰化和非乙酰化的重组COX-II体外制备羟基-DHA化合物。简而言之,采用重组人COX-II制备培养混合物,纯化后作为SF9细胞表达的COX-II的一种膜制备物。将该酶悬浮于400μl 1M的Tris缓冲盐(pH8.0),其中含5mM苯酚。COX-II的阿司匹林乙酰化为:向混合物中加入阿司匹林(2mM),37℃培养5分钟。加入400μl冷甲醇终止反应。然后用固相萃取柱(SepPak C18)萃取产物。
新的DHA化合物:13-羟基-DHA,14-羟基-DHA,16-羟基-DHA,17-羟基-DHA,19-羟基-DHA或20-羟基-DHA的效力与前述EPA所得产物相当,即,类似于图9A和9C所示结果。
本领域技术人员只需通过常规实验即可发现还有其他实施方式可获得与以上所述相似的技术效果,因此,这些都应包含在本发明的权利要求中。本发明全面参考了包括“发明背景”部分所提及的所有出版物和参考文献。
Claims (9)
2.如权利要求1所述的化合物,R是氢原子。
4.如权利要求3所述的药物组合物,R是氢原子。
6.如权利要求5所述的用途,所述药物用于治疗或预防关节炎或动脉炎。
7.如权利要求5所述的用途,其特征在于,所述药物用于治疗眼睛炎症、哮喘、肺炎或肺纤维变性。
9.如权利要求5-8中任一项所述的用途,其中,R是氢原子。
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