CN1430512A - 骨形成的调节 - Google Patents
骨形成的调节 Download PDFInfo
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- CN1430512A CN1430512A CN01807911A CN01807911A CN1430512A CN 1430512 A CN1430512 A CN 1430512A CN 01807911 A CN01807911 A CN 01807911A CN 01807911 A CN01807911 A CN 01807911A CN 1430512 A CN1430512 A CN 1430512A
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- bone
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Abstract
过氧化物酶体增生剂所激活的受体(除PPARγ以外)的激活剂或配体或该激活剂或配体的药学上可接受的衍生物在制备治疗或预防骨疾病的药物中的用途,该药物首次使骨组成代谢在增加骨沉积有益的情况时促进骨的沉积。相反,也容易抑制和/或阻滞骨沉积。
Description
本发明涉及可调节过氧化物酶体增生剂所激活的受体(PPAR’s)的活性的药剂在治疗方面的用途,并且还涉及这种药剂的检测。
哺乳动物的骨骼具有许多功能,例如提供支持、保护内脏器官以及提供连接肌肉和腱的部位而使动物移动的操作功能。骨在生长和发育过程中是一直被再吸收、替换和重建的活性组织。在哺乳动物的发育期骨架的生长是与哺乳动物的各种器官系统的生长和发育相协调时,这是相当普遍的。当成人骨骼形成时,它需要不断地维持以确保足够地维持它的功能。
骨组织的沉积、再吸收和/或重建是由特殊的合成细胞称之为成骨细胞(骨组织的沉积中所涉及)和分解细胞称之为破骨细胞(骨组织的再吸收和/或重建所涉及)来完成。这些特殊细胞的活性在生长和发育中是变化的。在人的早期正常发育中,新的骨组织的形成快于老骨的吸收,造成骨变大、变重和变得更致密。在完全发育的成人中,在最近20岁达到最大骨密度。但是,在晚年生活中,破骨细胞的活性超过了成骨细胞,造成骨密度的下降,结果骨质量下降。
在早期发育和/或晚年生活中会造成骨形成异常和严重后果的疾病有许多。这类型的疾病包括骨质疏松、骨硬化症、低磷酸酯酶症、成骨不全、佩吉特疾病、聋症和造成癌症的高钙血症。
到目前为止最普通的骨疾病是骨质疏松。骨质疏松是特征为骨组织变得稀薄和结构完整性损失会使骨骼变得容易骨折,尤其是脊柱、手腕或臀部的疾病。世界上有高达200百万人患有骨质疏松并且每年在欧洲、美国和日本有700,000人患有臀部骨折。其中20%在6个月内死亡并且50%无法返回到完全独立的生活状态。
妇女更容易患骨质疏松,但其他导致其的因素包括瘦和/或小、年龄、偶然性和遗传因素。此外,激素水平异常(例如在女性中雌激素水平低、在雄性中睾酮水平低)和钙和/或维生素D的缺乏也是导致其的因素。但这些无法控制,可控制的因素包括有习惯于久坐的生活方式、早期绝经、神经性厌食或贪食、闭经、某些治疗剂(例如皮质类固醇、抗惊厥药)、吸烟和酗酒。预防措施包括体育锻炼、确保饮食中的钙足够和维生素D的补充。
其他物质给成年动物给药时也显示出促进骨形成的作用,这些物质包括甲状旁腺激素(PTH)、前列腺素E2(PGE2)和1,25-(OH)2-维生素D3[1,25-(OH)2-D3]。但是,这些都伴有副作用而局限了它们的临床应用。例如,已经发现PGE2与自发性流产、腹泻和循环性虚脱有关;而1,25-(OH)2-维生素D3会引起高钙血症造成肾钙化;并且必须注射给药的PTH会引起少量的高钙血症。Raloxifene和alendronate都是可以使用的,但是伴有副作用,包括脸红、深度静脉血栓、腹部或肌肉骨骼疼痛、恶心、胃灼热或对食管的刺激。
激素替代疗法(HRT)已经用来治疗绝经骨质疏松,但是雌激素和降钙素(HRT成分)二者都有风险和/或副作用。雌激素会增加子宫内膜癌的风险,而降钙素会引起脸手的潮红、排尿增加、恶心和皮肤疹。
显然,现有的治疗骨质疏松的疗法尽管有效促进骨沉积或抑制过量的骨再吸收,但是却具有不可接受的副作用,限制了它们的临床应用。所以,仍然需要有效的疗法。
造成骨形成异常的其他疾病有佩吉特疾病。这种疾病一般会造成骨变大和形不成骨,导致骨的变软,骨折增加、骨疼痛和关节炎。佩吉特疾病的相关症状是听力的丧失。佩吉特疾病的起因还没有清楚地阐明。高达40%的患者都有该疾病的家族史,但是也有数据支持佩吉特疾病的病毒病因说。伴有骨质疏松时,缓解佩吉特疾病症状的疗法包括体育锻炼和服用降钙素或双磷酸酯。
甲状旁腺机能亢进是一种甲状旁腺活动过度并产生太多甲状旁腺激素而导致骨损失的激素疾病。PTH可以促进钙从骨中释放并调节钙从食品中的吸收。与甲状旁腺机能亢进有关的症状包括昏睡、疲劳、肌肉变弱、关节疼痛和便秘,并且钙在血浆中的高浓度也会造成钙在肾脏中的沉积,形成结石。该疾病的起因目前还不清楚。一般疗法是摘除一个或多个甲状旁腺,但这会造成不可逆的和无法治愈的甲状旁腺功能减退。
成骨不全(OI)是一种特征为骨易碎的疾病,并且起因于骨组织产生胶原的能力异常或降低。不同类型的严重程度和影响是不同的,最轻度类型的特征是容易骨折、脊柱有弯曲倾向、牙齿易碎和听力丧失。目前还不能治愈,并且该疗法是通过物理疗法将症状降低到最小并减少骨折的可能性。已经报导的有希望的结果是双膦酸盐,尤其是在生长中的儿童,但是这些试验还没有进行双盲或安慰剂对照。
称作为磷酸酯酶过少的相关基因遗传疾病与OI有许多共同的症状。在这些疾病严重时,个体不能在子宫中形成骨骼而流产。在较轻时,例如牙齿磷酸酯酶过少症,该疾病表现为牙齿过早脱落。对磷酸酯酶过少症还没有疗法。
其他疾病也对骨形成有直接影响。特别重要的是癌症,它能够造成高钙血症,并且最后形成易碎的骨。
过氧化物酶体增生剂激活的受体(PPAR’s)是一组位于细胞核控制涉及脂质体内平衡的基因表达的激素受体。PPAR’s已显示出对许多通过增加了的包含该酶表达在该过氧化物酶体内促进过氧化物酶体的复制和代谢脂肪酸能力的化合物有反应。
PPARα是该族特征化的第一成员[Isseman & Green(1991),Nature,347:645-650],它被许多刺激涉及过氧化物酶体β氧化的基因表达的中等和长链脂肪酸激活。PPARα通过DNA上游促进剂成分对脂质起作用并已经显示出可与视网膜样的受体形成杂二聚糖[Kliewer等(1992),Nature,358:771-774],该络合物已经显示出与促进剂结合并激活RNA聚合酶II转录。
因为识别出了PPARα,PPAR族的其他成分包括PPARγ(Kliewer等,Proc.Nat.Acad.Sci.USA,91:7355-7359)和PPARδ[Lim H.,等(1999),环状氧化酶-2-衍生的前列腺素通过PPARδ调节鼠的胚胎移植]也已经被鉴别。这些PPAR相应物的每一种都已经显示出结合许多能够通过PPAR基因特殊转录诱发过氧化物酶体复制/活性的化合物。
显示出结合PPAR相应物的许多试剂已经表现出有治疗潜力。例如,WO 99/32465描述了能够结合PPARα、δ和/或γ的芳基噻唑烷二酮衍生物并且它可以用于治疗或预防糖尿病、高血糖症、高脂血症、动脉粥样硬化症或肥胖症。
除了普通的PPAR激动剂外,已经识别出许多特殊试剂,被称为特异性激活特殊PPAR转录因子。例如,WO97/36579公开了用于治疗肥胖症的PPARα拮抗药。WO 97/28149公开了用于提高高密度的脂蛋白血浆浓度的PPARδ激动剂的化合物,由此对抗动脉粥样硬化的心血管病的进程。US-A-5925657公开了PPARγ激动剂在抑制通常与风湿性关节炎有关的炎性反应相关的细胞素产生的用途。
WO 99/10532公开了识别PPAR激动剂和PPAR拮抗药两种的方法从而识别可用于调节PPAR相应物的活性的试剂。
EP-A-783888公开了troglitazone和相关噻唑烷二酮在生产治疗和预防骨质疏松的药物方面的用途,尽管没有证实骨组织的合成代谢的活性。
WO 00/27832是中间文件并公开了可用于治疗骨质疏松的PPARγ拮抗药。
WO 00/23451是中间文件并公开了用于治疗和/或预防由PPAR’s调节的疾病尤其是血脂过少和糖尿病的取代的三环化合物。
JP-A-2022226公开了前列腺素D和J类似物用于治疗骨疾病的用途,证实了对成骨细胞有积极作用。没有提到对PPAR有任何作用。
WO 00/18234是中间文件并公开了噻唑烷二酮作为PPARγ激动剂与治疗剂组合治疗肿瘤。肿瘤减少了但没有显示出骨合成代谢活性。
Okzazki等[Endocrinology,(1999),140(11):5060-5]报导了涉及一组可体外抑制骨髓基质细胞(BMSC’s)形成成骨细胞的噻唑烷二酮化合物(PPARγ激动剂)。暴露给噻唑烷二酮的BMSC’s可诱导脂肪细胞的形成并抑制了成骨细胞的形成。
在损害成骨细胞形成的情况下,PPAR激动剂涉及了脂肪细胞的分化,这些公开在Johnson等[Endocrinology(1999),140(7),第3245页]。成骨细胞和脂肪细胞二者都起源于骨髓的间充质干细胞,并促进了一个生成抑制了其他生成。糖皮质类固醇受体已经显示有预成骨细胞活性,在本文PPAR配体显示了促进脂肪细胞的分化。
Johnson等描述了一种PPARγ激动剂TZD,[5-(4-{[N-甲基-N(2-吡啶基)-氨基]乙氧基}苄基)噻唑烷-2,4-二酮]与地塞米松(糖皮质激素)组合对一种成骨细胞细胞系MB-1.8细胞的作用。MB-1.8,当暴露于TZD时,显示出碱性磷酸酯酶活性和与成骨细胞相关基因的表达都下降,同时提高了脂肪细胞的脂肪酸蛋白的表达。地塞米松对抗TZD对碱性磷酸酯酶和成骨细胞基因标记表达的作用,但是增加了脂肪细胞的脂肪酸蛋白的表达。这样,再次显示出PPAR激动剂在损害成骨细胞分化的情况下可促进脂肪细胞分化。
所以,已经确立了当PPAR’s活性的主要区域是在脂质体内平衡时,它们也能够对骨代谢具有作用。这种作用似乎是通过影响骨中的干细胞的分化产生,并在激活的PPAR在损害成骨细胞的情况下利于脂肪细胞形成上只显示出阴性。这根本不必惊讶,假定PPAR’s在脂质体内平衡具有活性时,肯定是PPARγ激动剂例如已经研究至今的proglitazone。
还显示出降低成骨细胞数的可能性,由此减缓骨吸收,但是到诊断出骨质疏松时,患者已经丧失了50%的骨质量,所以,对不是静止疗法的可能通过预防更多成骨细胞产生获得治疗的一种再生疗法有一种需求。
出人意料地是,我们现在已经发现PPARα和PPARδ不仅包括在脂质体内平衡中,而且也通过成骨细胞调节骨形成,当适当激活时,实际上提高了成骨细胞的活性。
这样,第一方面,本发明提供了除PPARγ以外的过氧化物酶体增生剂激活的受体的激活剂或配体或所述激活剂或配体的药学上可接受的衍生物在制备治疗或预防骨疾病的药物中的用途。
在另外一方面,提供了至少一种可调节至少一种PPAR转录因子活性的试剂在制备治疗至少一种骨疾病的药物中的用途。
本文所用的术语“激活剂”是指可激活PPAR的物质。这类物质可以直接激活PPAR,或者可以在体内代谢以形成配体通过与PPAR结合激活PPAR。
已知某些物质是总-激活剂或总-激动剂,可以激活全部PPAR’s,这些物质本身不需要结合受体。这类物质包括在本发明的范围内,条件是由激活的PPAR导致的成骨细胞活性大于正常,最好就象用本文以下所述的本发明试验所测定的。用于本发明的优选总-激动剂包括亚油酸、亚麻酸和花生酸。
已知本发明的激活剂或配体的药学上可接受的衍生物可以在需要时使用。这类衍生物可以是药物前体、配体或激活剂的盐或酯的形式,并且在它们自身形式是有活性的。优选的盐是简单盐类如盐酸盐、硫酸盐或醋酸盐。优选的酯包括乙酯和甲酯,同时适当的药物前体包括化合物的糖苷。
已知PPAR至少有三种类型即PPARα、PPARγ和PPARδ。在该族中还有其他受体,并且也包括在本发明的范围内。
已知用于本发明的化合物是可与PPAR’s结合的或激活PPAR’s的那些化合物,并且它们全部包括在本发明中,只要它们能够结合或激活不是或除了PPARγ以外的PPAR。
也已知本发明可以扩大到本文所公开的新化合物。
在优选的实施方案中,所用的化合物是PPAR拮抗剂并且可以用于治疗佩吉特疾病。
尽管如此,还是特别优选用于本发明的化合物是PPAR’s的激动剂或激活剂。除PPARγ以外的PPAR’s激动剂促进成骨细胞的活性并且是用于治疗患者患有降低的或不足的骨质量如骨质疏松的疾病。以前的治疗只是静止的,但是本发明的该实施方案的化合物可以使骨再生。
优选类的化合物是可激活PPARα或PPARδ的那些化合物。
还优选的是fibrate。一些fibrate可以激活PPARγ,但是非诺贝特是PPARα的激动剂,而苯札贝特是PPARδ的激动剂。这些化合物的任何一种分别都是优选的。
对本领域普通技术人员显而易见的是术语激动剂是指一般可促进PPAR转录因子活性的一组药剂。所以,使用术语拮抗药是指任何可抑制PPAR转录因子的转录活性的药剂。
在本发明另外优选的实施方案中,激动剂是fibrate或N-(2-苯甲酰苯基)-L-酪氨酸衍生物。只作为PPARγ激动剂的Glitazone不是本发明的一部分,并且只有当glitazone作为其他PPAR’s的激动剂或拮抗药时它才是优选的。
下列药剂全部都是优选的:3-{4-[2-(2-苯并噁唑基甲基氨基)乙氧基]苯}-2-(2S)-(2,2,2-三氟乙氧基)丙酸;二十二碳六烯酸;LY171883;亚油酸;油酸;棕榈酸;氯贝特;二十碳四烯酸;8(S)-羟基-6,8,11,14-二十碳四烯酸;棕榈酸甲酯;Wy-14643([4-氯-6-(2,3-二甲代苯氨基)-2-嘧啶基硫代]醋酸);萘苯丁酸{2-甲基-2[p-(1,2,3,4-四氢-1-萘基)苯氧基]丙酸};祛酯酸[2-甲基-2([p]-氯苯氧基)-2-甲基丙酸];MK-571((+-)-3-[({3-[2-(7-氯-2-喹啉基)乙烯基]-苯基}{[3-(二甲基氨基)-3-氧丙基]硫代}甲基)-(硫代)(丙酸);PGJ(2)[前列腺素J2];Δ(12)前列腺素J2];15-脱氧-Δ(12,14)-PGJ(2)[15-脱氧-Δ(12,14)前列腺素J2];PD19559;共轭亚油酸;carbaproscyclin;9-羟基十八碳二烯酸;KRP-297;伊洛前列素;L783483;岩芹酸;反油酸;芥酸;亚麻酸;L165461;L796449;L165041;GW2433;GW1929;GW2331;2-溴棕榈酸盐;庚-4-炔基-VPA(庚-4-炔基-丙戊酸);己-4-炔基-VPA(己-4-炔基-丙戊酸);棕榈酸甲酯;4-[3-(2-丙基-3-羟基-4-乙酰基苯氧基)丙氧基]-苯氧乙酸;3-氯-4-{3-[2-丙基-3-羟基-4-(1-羟基亚氨基(hydroxlimino)丙基)-苯氧基]丙基硫代}苯基醋酸;3-氯-4-[3-(3-乙基-7-丙基-6-苯并[4,5]-异噁唑)丙基硫代]苯基醋酸;3-氯-4-[3-(2-丙基-3-三氟甲基-6-苯并[4,5]异噁唑)丙基硫代]苯基醋酸;4-(2-乙酰基-6-羟基十一烷基)肉桂酸;3-氯-4-[3-(3-苯基-7-丙基苯并呋喃-6-基氧)丙基硫]苯基醋酸;和3-丙基-4-[3-(3-三氟甲基-7-丙基-6-苯并[4,5]-异噁唑氧基)丙基硫代]苯基醋酸。
治疗优选的目标分别是骨质疏松、佩吉特疾病、成骨不全、磷酸酯酶过少症、甲状旁腺机能亢进、耳聋、牙异常、或者导致高钙血症的癌症尤其是骨髓瘤。
骨质疏松目标优选是绝经后骨质疏松、雄性骨质疏松或激素所诱发的骨质疏松,特别是在用糖皮质激素所诱发的时候。
本发明还设想治疗易于或具有骨疾病的哺乳动物优选是人的方法,它包括给予药学上有效量的本发明激活剂或配体。
本发明还提供了本文所述配体和激活剂的药物制剂,尤其是这种制剂以前没有公开治疗用途。
已知治疗制剂可以制成任何适当的形式,并且可以使用任何药学上可接受的载体。这将取决于用于该制剂化合物的性质,依次是该制剂是药物前体、盐或酯的形式。
适当的载体简单来说只是水或盐水,但它一般优选化合物全身给药。例如这可以是通过注射、时间释放胶囊/片或者经皮贴剂。这些当中的全部适当的制剂在本领域中都是公知的,对本领域普通技术人员来说是显而易见的。
在本发明优选的实施方案中,药物包括至少一种载体和/或赋型剂。理想的载体或赋型剂起调节稳定性和/或使药剂靶向到优选的活性部位,一般是骨组织的作用。靶向的适当载体和/或赋型剂是本领域所熟知的,包括对选择性细胞类型所分别表达的多肽特异性的抗体;和脂质体如称之为STEALTH脂质体。其他适当的靶向物质可以搀和到含有配体或激活剂的囊、脂质体或胶粒,并且可以在通常接近需要激活相关PPAR的区域包括靶向的配体或抗体。
已知抗体可以是多克隆或单克隆,或者可以只含有其有效的或等量的部分(例如FAB片段)。人化的单克隆抗体或其片断或等同物是特别优选的。用于生产人化的单克隆抗体的方法在本领域中是熟知的。
脂质体是囊中包裹有导入给患者的选择性药剂的基于脂质的囊。该脂质体可以从纯磷脂或磷脂的混合物和磷酸甘油酯中生产。一般来说,脂质体可制成小于200nm的直径,使其可以静脉注射并通过肺毛细管床。而且脂质体的生化性质赋予穿过血管膜到达所选组织的渗透性。脂质体具有相对短的半衰期。目前已经开发出称之为STEALTHR的脂质体,它含有用聚乙二醇(PEG)包衣的脂质体。用PEG处理的脂质体在静脉给予患者时有显著增加了的半衰期。
当需要时,可以给患者使用制剂。在任何情况下,有技术的医生将很容易地开出有效剂量和给药方案的处方。给药剂量取决于受体的年龄、健康和体重、共用的疗法的类型(如果有),该疗法的频率和所需作用的性质。例如全身每日剂量是大约0.1mg到大约500mg。正常地,在一个或多个每日剂量中大约10mg到100mg的激活剂或配体在获得所需结果时是有效的。
对骨合成代谢药物作用的细胞基础缺乏理解的主要原因是目前没有以适当方式对这些药物的反应进行单独体外测定。但是,我们现在已经开发出了许多测定法,当与新生鼠的颅盖器官培养物结合使用时,这些测定法能够预测骨合成代谢药剂。
这样,按照本发明的又一方面,提供了用于筛选可调节PPAR转录因子活性的药剂的方法,它包括:
i提供骨形成细胞的培养基;
ii把骨形成细胞暴露给可调节至少一种PPAR转录因子活性的药剂;并且
iii监控该药剂对细胞培养基的骨形成能力的作用。
这种类型的筛选在本领域中是熟知的,但没有用于筛选可调节PPAR转录因子活性的药剂。例如,这些包括钙化的成纤维细胞-集落形成单位测定法(Scutt A.Bertram P.骨髓细胞是前列腺素E2的合成代谢作用于骨的目标物:从非粘连向粘连成骨细胞前体转移的诱导。J.Bone and MineralRes.10:474-489,1995);非粘连基质前体细胞培养基的筛选(Miao D,ScuttA.非粘连基质前体细胞是骨合成代谢药剂的目标物,J Bone and Miner.Res.23:S537,1998)和颅盖胶原合成的筛选,用于监控胶原的产生[ChyunY.S.,Raisz L.G.,(1984)前列腺素E2对骨形成的刺激,前列腺素27:97-103]。
按照本发明的另外一个方面,提供了一种由本发明筛选方法所导出的药剂。
在附图中,它们完全是详细说明而不是限定本发明,某些化合物分别在碱性磷酸酶活性、钙吸收和胶原合成上显示出作用,其中最后的条柱显示了累积的和测定的化合物对骨合成代谢的作用。
图1是PGA1的条形图;
图2是非诺贝特的条形图;
图3是苯札贝特的条形图;
图4是亚油酸的条形图;
图5是PGA2的条形图;
图6是油酸的条形图;并且
图7是芝麻素的条形图。
本发明现在用下列非限定型实施例进行进一步的详细说明。
预备实施例
在测试化合物前,必须准备该测试法。所用的物质和测试法的准备如下。全骨髓细胞的制备
从125g雄性Wistar大鼠的胫骨和股骨中获得全骨髓细胞(BMC’s)。在无菌条件下除去骨并除去所有粘连的软组织。摘除每根骨的一端,在另一端用18号注射针头作孔,并离心分离细胞[Dobson K.R.,等,Calcif.Tissue Int.,65:411-413(1999)]。通过反复移液将细胞分散于10ml的DMEM中(含有12%FCS,1×10-8M地塞米松和50mg/ml抗坏血酸),经过用20号注射针头用力排除细胞获得单细胞悬浮液。然后将细胞用于下述方法中。成骨细胞集落形成单位培养基
为了分析在全BMC或高密度的非粘连基质前体(NASP)细胞培养基中的成骨细胞-集落形成单位(CFU-f)的数量,将106有核的BMC或来自高密度NASP细胞培养基的非粘连细胞平板接种在含有12%FCS、1×10-8M地塞米松和50μg/ml抗坏血酸的DMEM的55cm2培养皿上。在全BMC的CFU-f分析中,一旦培养期开始就加入试验药剂。在NASP细胞培养基中,在NASP细胞培养自身开始时加入试验药剂并且CFU-f测定只用于测定在NASP细胞培养过程中所产生的CFU-f数量。5天后更换培养基,之后一周更换两次。将培养基保持18天,之后将细胞用PBS洗涤并通过加入冷乙醇固定。
固定后,将培养基染色,碱性磷酸酶(Apase)为阳性、钙为阳性、胶原为阳性并且总集落如Scutt & Bertram所述(J.Bone and Mineral Res.10:474-489,1995)。然后使用数码相机给培养基拍照用Bioimage“智能计数器”图像分析软件对APase阳性、钙阳性、胶原阳性和总集落定量[DobsonK.,等,一种自动定量分析含有潜在成骨细胞的成骨细胞-集落形成单位的有效方法,Calcif.Tissue Int.65:166-172(1999)]。高密度的NASP细胞的培养
在含有12%FCS、10-8M地塞米松和50μg/ml抗坏血酸的DMEM的孔中以每2cm2有1.5×106个细胞数的密度培养BMC。将被测试药剂的溶液加入到孔中,然后培养4天。接着按照上述CFU-f培养的方法给上清液中存在的NASP细胞数定量。为了这些操作,将培养基轻轻摇晃并将含有非粘连细胞的上清液转移到55cm2培养皿中。加入含有12%FCS、10-8M地塞米松和50μg/ml抗坏血酸的10ml的DMEM并如CFU-f培养所述进一步维持该培养基。新生大鼠颅盖的器官培养
杀死一天龄的幼鼠并将颅盖(头骨)解剖。然后沿矢状缝将颅盖切成每胎两半。每个骨都在2ml含有1mg/ml BSA、50μg/ml抗坏血酸、60μg/ml青霉素和50μg/ml链霉素和1×10-8M的地塞米松的DMEM的35mm组织培养基孔中培养。24小时后,培养基用新鲜培养基取代,加入任何测试药剂,并将组织再培养48小时。胶原合成的测定法
在该测定方法中,在培养期结束时对每只骨都用10μCi的[3H]脯氨酸脉冲24小时。将这些骨用三氯乙酸(TCA)、丙酮和乙醚连续冲洗,然后干燥。用纯化的细菌胶原酶通过Peterkofsky B.和Diegelmann R.的方法(Biochemistry,6:988-994,1971)测定掺入到胶原酶消化的蛋白(CDP)中的[3H]脯氨酸并表示为dpm。
实施例
PGE2可以通过非酶化转化成A系列的前列腺素(由Negushi N.,等Lipid Mediators Cell Signalling 12,443-448,1995所综述),并且PGE2的合成代谢活性可以由这些代谢产物调节。所以,按照上述测定方法测定PGA1,并发现在所有测试法中的三种产生了阳性反应。结果,如图1所示,是相当于PGE2所产生的数值,显示出骨的合成代谢活性。
从对其他化合物的试验结果中可以看出,fibrate族的化合物都具有骨合成代谢活性,不管PPAR是否与它们相互作用。例如,非诺贝特(图2)结合PPARα,而苯札贝特(图3)结合PPARδ。二者都有优于PGE2的活性。
如上所示,PGA1,已知是潜在的PPARδ激动剂,会产生显著的依赖剂量的集落数增加。棕榈酸甲酯也产生刺激。其他PPARδ激动剂,伊洛前列素也产生相当于PGA1的刺激作用。
亚油酸(图4),已知可以结合所有的PPAR’s,也显示出骨合成代谢活性。
其他显示出有用活性的化合物是PGA2(图5)、油酸(图6)和芝麻素(图7)。一般,显示出有用活性的化合物被认为是具有相当于PGE2活性的那些化合物,尽管可以认为具有超过不含化合物的对照活性的任何化合物相对于现有技术来说也是较好的。
以前最有效的骨合成代谢药剂是PGE2。但是,因为PGE2受体是普遍存在的,使用它会产生许多严重的并发症包括呕吐、腹泻、自发流产和最严重循环衰弱。但是,PGE2的代谢物PGA1具有至少如PGE2一样好的活性水平。PGA1不会结合细胞膜受体,这样不可能引起PGE2所见的副作用。
如上所述,还没有能够对骨合成代谢活性进行可信性报导的单一测定法。个别测定法能够鉴别出某些假定的骨合成代谢剂,但是当许多骨合成代谢剂有许多机理起作用时,大多数仍无法鉴别。使用CFU-f和NASP细胞测定法并结合新生大鼠颅盖器官培养基,骨合成代谢剂就能够可信地鉴别,把假阴性减少到最小值。
Claims (16)
1.一种化合物在制备治疗或预防骨疾病的药物的用途,其中所述化合物为除PPARγ以外的过氧化物酶体增生剂所激活的受体的激活剂或配体或所述激活剂或配体的药学上可接受的衍生物。
2.按照权利要求1的用途,其中激活剂是总激活剂。
3.按照权利要求2所述的用途,其中该激活剂是亚油酸、亚麻酸或花生四烯酸。
4.按照权利要求1所述的用途,其中配体是激动剂。
5.按照权利要求4所述的用途,其中配体是PPARα或PPARδ的激动剂。
6.按照前面任一权利要求所述的用途,其中该物质具有等于或大于PGE2的骨组成代谢活性。
7.按照权利要求1所述的用途,其中该物质是拮抗剂。
8.按照权利要求7所述的用途,其中骨疾病是佩吉特疾病。
9.按照权利要求1所述的用途,其中该物质是fibrate。
10.按照权利要求9所述的用途,其中该物质是非诺贝特或苯札贝特。
11.按照权利要求1所述的用途,其中该物质是N-(2-苯甲酰苯基)-L-酪氨酸衍生物。
12.按照权利要求1所述的用途,其中该物质是PGA1、PGA2或芝麻素。
13.按照权利要求1所述的用途,其中3-{4-[2-(2-苯并噁唑基甲基氨基)乙氧基]苯}-2-(2S)-(2,2,2-三氟乙氧基)丙酸;二十二碳六烯酸;LY171883;亚油酸;油酸;棕榈酸;氯贝特;二十碳四烯酸;8(S)-羟基-6,8,11,14-二十碳四烯酸;棕榈酸甲酯;Wy-14643([4-氯-6-(2,3-二甲代苯氨基)-2-嘧啶基硫代]醋酸);萘苯丁酸{2-甲基-2-甲基-(1,2,3,4-四氢-1-萘基)苯氧基]丙酸};祛酯酸[2-甲基-2([p]-氯苯氧基)-2-甲基丙酸];MK-571((+-)-3-[({3-[2-(7-氯-2-喹啉基)乙烯基]-苯基}{[3-(二甲基氨基)-3-氧丙基]硫代}甲基)-(硫代)(丙酸);PGJ(2)[前列腺素J2];Δ(12)前列腺素J2];15-脱氧-Δ(12,14)-PGJ(2)[15-脱氧-Δ(12,14)前列腺素J2];PD19559;共轭亚油酸;carbaproscyclin;9-羟基十八碳二烯酸;KRP-297;伊洛前列素;L783483;岩芹酸;反油酸;芥酸;亚麻酸;L165461;L796449;L165041;GW2433;GW1929;GW2331;2-溴棕榈酸盐;庚-4-炔基-VPA(庚-4-炔基-丙戊酸);己-4-炔基-VPA(己-4-炔基-丙戊酸);棕榈酸甲酯;4-[3-(2-丙基-3-羟基-4-乙酰基苯氧基)丙氧基]-苯氧乙酸;3-氯-4-{3-[2-丙基-3-羟基-4-(1-羟基亚氨基丙基)-苯氧基]丙基硫代}苯基醋酸;3-氯-4-[3-(3-乙基-7-丙基-6-苯并[4,5]-异噁唑)丙基硫代]苯基醋酸;3-氯-4-[3-(2-丙基-3-三氟甲基-6-苯并[4,5]异噁唑)丙基硫代]苯基醋酸;4-(2-乙酰基-6-羟基十一烷基)肉桂酸;3-氯-4-[3-(3-苯基-7-丙基苯并呋喃-6-基氧)丙基硫]苯基醋酸;或者3-丙基-4-[3-(3-三氟甲基-7-丙基-6-苯并[4,5]-异噁唑氧基)丙基硫代]苯基醋酸。
14.按照前面任一权利要求所述的衍生物的用途,它是药物前体、盐或酯。
15.按照前面任一权利要求所述的用途,其中骨疾病是骨质疏松症、佩吉特疾病、成骨不全、低磷酸酯酶症、甲状旁腺机能亢进、聋症、牙异常、或者导致高钙血症特别是骨髓瘤的癌症。
16.一种用于筛选能调节PPAR转录因子活性的药剂的方法,包括:
i提供成骨细胞的培养基;
ii把成骨细胞暴露于能调节至少一种PPAR转录因子活性的药剂;并且
iii监控该药剂对细胞培养基骨形成能力的作用。
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JPH09295936A (ja) * | 1996-04-30 | 1997-11-18 | Kowa Techno Saac:Kk | 人工透析患者の骨疾患治療用外用剤 |
US5804210A (en) * | 1996-08-07 | 1998-09-08 | Wisconsin Alumni Research Foundation | Methods of treating animals to maintain or enhance bone mineral content and compositions for use therein |
US5925657A (en) * | 1997-06-18 | 1999-07-20 | The General Hospital Corporation | Use of PPARγ agonists for inhibition of inflammatory cytokine production |
EP1028724A1 (en) * | 1997-11-10 | 2000-08-23 | Novo Nordisk A/S | Transdermal delivery of 3,4-diarylchromans |
GB9824614D0 (en) * | 1998-11-11 | 1999-01-06 | Glaxo Group Ltd | Chemical compounds |
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2000
- 2000-02-15 GB GBGB0003310.0A patent/GB0003310D0/en not_active Ceased
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2001
- 2001-02-15 HU HU0204511A patent/HUP0204511A3/hu unknown
- 2001-02-15 WO PCT/GB2001/000626 patent/WO2001060355A1/en not_active Application Discontinuation
- 2001-02-15 US US10/203,695 patent/US20030139372A1/en not_active Abandoned
- 2001-02-15 AU AU32121/01A patent/AU3212101A/en not_active Abandoned
- 2001-02-15 MX MXPA02007901A patent/MXPA02007901A/es unknown
- 2001-02-15 CN CN01807911A patent/CN1430512A/zh active Pending
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- 2001-02-15 IL IL15124301A patent/IL151243A0/xx unknown
- 2001-02-15 KR KR1020027010501A patent/KR20020093808A/ko not_active Application Discontinuation
- 2001-02-15 CZ CZ20022741A patent/CZ20022741A3/cs unknown
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- 2001-02-15 JP JP2001559453A patent/JP2003522787A/ja not_active Abandoned
- 2001-02-15 BR BR0108344-9A patent/BR0108344A/pt not_active IP Right Cessation
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2002
- 2002-08-07 ZA ZA200206318A patent/ZA200206318B/xx unknown
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105327333A (zh) * | 2015-10-30 | 2016-02-17 | 大连大学 | 可促进牙种植体周围成骨的口腔施用组合物及其制剂 |
CN105327333B (zh) * | 2015-10-30 | 2018-09-07 | 大连大学 | 可促进牙种植体周围成骨的口腔施用组合物及其制剂 |
CN110433156A (zh) * | 2019-08-27 | 2019-11-12 | 成都元素平衡生物科技有限公司 | 芝麻素在成骨分化中的新应用 |
WO2022041311A1 (zh) * | 2020-08-31 | 2022-03-03 | 苏州大学 | 2-溴棕榈酸在制备防治骨丢失相关疾病的药物中的应用 |
Also Published As
Publication number | Publication date |
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NO20023837D0 (no) | 2002-08-14 |
HUP0204511A2 (en) | 2003-05-28 |
ZA200206318B (en) | 2003-11-07 |
NO20023837L (no) | 2002-10-14 |
EP1259233A1 (en) | 2002-11-27 |
HK1049618A1 (zh) | 2003-05-23 |
CZ20022741A3 (cs) | 2003-03-12 |
AU3212101A (en) | 2001-08-27 |
WO2001060355A1 (en) | 2001-08-23 |
US20030139372A1 (en) | 2003-07-24 |
GB0003310D0 (en) | 2000-04-05 |
CA2399810A1 (en) | 2001-08-23 |
JP2003522787A (ja) | 2003-07-29 |
KR20020093808A (ko) | 2002-12-16 |
BR0108344A (pt) | 2003-03-11 |
HUP0204511A3 (en) | 2004-11-29 |
IL151243A0 (en) | 2003-04-10 |
NZ520764A (en) | 2004-05-28 |
MXPA02007901A (es) | 2004-09-10 |
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