CN100369891C - Hif羟化酶抑制剂 - Google Patents
Hif羟化酶抑制剂 Download PDFInfo
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- CN100369891C CN100369891C CNB038109557A CN03810955A CN100369891C CN 100369891 C CN100369891 C CN 100369891C CN B038109557 A CNB038109557 A CN B038109557A CN 03810955 A CN03810955 A CN 03810955A CN 100369891 C CN100369891 C CN 100369891C
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Abstract
本发明提供如本文定义的式(A)、(B)、(C)、(D)、(E)、(F)之一的化合物或其盐,其用于治疗与HIF水平或活性提高或减低有关的病症、或HIF水平或活性提高或减低会对其有利的病症。
Description
发明领域
本发明涉及调节2OG(2-氧代戊二酸)依赖性加氧酶、尤其是脯氨酰羟化酶的化合物。这些化合物可用作HIF(低氧诱导因子)α(HIF-α)脯氨酰羟化酶的调节剂。
发明背景
转录因子HIF(低氧诱导因子)系统是对低氧反应的关键调节系统,在很多种生物体内的氧稳态中占有主要的地位。已鉴定出很多种转录靶标,它们在血管生成、红细胞生成、能量代谢、炎症、血管舒缩功能及凋亡/增殖反应中起到重要的作用。上述系统对正常发育来说是必需的,且其在对局部缺血/低氧的病理生理反应中起着关键的作用。HIF在癌症中也很重要,通常其在癌症中受到正调节,对肿瘤生长和血管生成具有主要的作用。HIF DNA结合复合体由α亚单位和β亚单位异二聚体组成。氧调节是通过对α亚单位的羟基化来进行的,α亚单位会被氧合细胞的蛋白酶体迅速破坏。这涉及vonHippel-Lindau肿瘤抑制蛋白(pVHL)对HIF-α亚单位的结合,其中pVHL作为泛素连接酶的识别成分或识别成分的一部分,所述识别成分通过与HIF-α亚单位中的特异性序列相互作用来促进泛素依赖性蛋白酶解作用。在低氧状况下,此过程被抑制,从而稳定HIF-α和容许通过HIFα,β的转录激活。
发明内容
在我们的英国专利申请第0118952.1号中,我们公开了包括以下多肽:
(a)具有HIF羟化酶活性,含有SEQ ID NO:2、4或6氨基酸序列的多肽;
(b)SEQ ID NO:2、4或6氨基酸序列的变体,具有至少60%的一致性,且具有羟化酶活性;或
(c)(a)或(b)的片断,其具有HIF羟化酶活性。
优选所述多肽具有脯氨酰羟化酶活性,且其活性需要Fe(II)。
从序列来看,所述多肽与其晶体结构已知的非血红素加氧酶如脯氨酸-3-羟化酶(Clifton等,Eur.J.Biochem,2001,268,6625-6636)有关。
上述专利还公开了编码所述多肽的多核苷酸以及包含所述多核苷酸的表达载体和能与所述多肽特异性结合的抗体。我们还公开了鉴定HIF羟化酶活性的调节剂的测试方法,以及调节剂如肽活性抑制剂在治疗以下病症中的用途:与健康(正常)水平相比由于HIF水平发生改变而导致的病症或疾病,以及HIF水平或活性改变会对其有利的病症。
2-OG依赖性酶——胶原脯氨酰-4-羟化酶(CPH)的抑制剂为本领域所公知,它们曾被建议用于治疗肺纤维化、皮肤纤维化(硬皮病)、动脉粥样硬化和其它与胶原生物合成有关的病症。对羟苯丙酮酸加氧酶(用亚铁作为辅因子的非血红素加氧酶)的抑制剂如三酮被用作除草剂(Lee D.等(1998)Pestic.Sci.54(4)377-384)。我们已公开,这些CPH抑制剂(及其它成分)中有些也能抑制PHD多肽的生物学(即HPH)活性。抑制PHD多肽的生物学活性的CPH抑制剂或修饰的CPH抑制剂可用于治疗与降低的或亚适的HIF水平或活性有关的病症,或治疗提高HIF水平或活性会对其有利的病症,例如局部缺血、伤口愈合、自体移植、异体移植和异种移植、系统性高血压、癌症、炎症和代谢紊乱。
已公开多种有关能抑制、增强、提高或刺激PHD多肽对HIF-α的羟化的调节剂的方法和用途。破坏、干扰或调节PHD多肽对HIF-1α的羟化的目的可以是调节细胞功能,如血管生成、红细胞生成、能量代谢、炎症、基质代谢、血管舒缩功能及凋亡/增殖反应和对局部缺血/低氧的病理生理反应,这些细胞功能如上所述均由HIFα介导。
调节2OG加氧酶尤其是CPH的化合物可用作HIF脯氨酰羟化酶的调节剂,或可用作‘前导’化合物,后者可被修饰和/或优化变成HIF脯氨酰羟化酶的调节剂尤其是选择性调节剂。
这些化合物中的一些通常具有下式:
R1A*B*C*D*(R2)y(A)
其中基团R1能与精氨酸残基的侧链发生静电作用,在催化过程中所述精氨酸残基与其它残基一起结合2-氧代戊二酸酯的5-甲酸酯基,A*B为由两个原子组成的能被官能化的链,所述两个原子可独立为碳、氧、氮、或硫,y为0或1,C*D为由两个原子组成的能被官能化的链,所述两个原子可独立为碳、氧、氮、或硫,A、B、C和D通过单键和/或双键和/或三键相互连接,这样,当y为0或1时,其中至少一个原子能与金属基团螯合,而当y为1时,所述链与能与金属基团螯合的R2连接。通常A、B、C和D至少有一个不为碳。典型的链包括C-N-C-C、C-O-C-C和C-C-C=O。链原子能构成环的一部分。
本发明发现了几类新的HIF脯氨酰羟化酶调节剂。它们具有下式(E)结构:
其中各R1可相同或不同,而且为H;OH;SH;任选含有1个或多个(如2个)N、S、O或P链原子、能被官能化的支链或直链C1-C6烷基链,尤其是甲基;任何氨基酸侧链如丙氨酸、苯丙氨酸、缬氨酸和谷氨酸侧链;任选含有1个或2个N、S、O或P原子的4-7元杂环,或任选含有1个或2个N、O或S原子、能与另一个环稠合的5元或6元芳环;或被所述芳环取代的所述烷基链,如芳氧基烷基;R11表示OH或R10NH,其中R10为HO、R1CO或为氨基酸残基H2N(R1R1C)CO-,其中各R1可相同或不同,定义同上;或R11代表HOOC(X)x,其中x为0或1,X为R1R1C,其中各R1可相同或不同,定义同上;n为1或2,R12为H或支链或直链C1-C6烷基;或其盐。通常X为CH2或CHOH。
因此,本发明提供式(E)化合物,其用于治疗与HIF水平或活性升高或减低有关的病症、或HIF水平或活性的提高或减低会对其有利的病症,本发明还提供式(E)化合物在制备用于治疗所述病症的药物中的用途。
所述烷基和链通常可用醇、氟、硫醇、羧酸、膦酸或次膦酸、磺酸或其它螯合基团进行官能化,在链的情况下,通常通过烷基进行官能化。
在本文所述的各结构式中,支链或直链C1-C6烷基链可以是甲基、乙基、丙基、丁基、异丁基、叔丁基、戊基、新戊基、叔戊基或伯己基、仲己基或叔己基。杂原子如O、S、N和P可取代一个或多个碳原子。优选烷基为甲基,优选的杂环为吡咯烷(pyrolidine)和四氢吡喃,优选的芳环为苯、萘和吡啶。
通常,各R1独立为H;OH;任选含有1个或多个N、S、O或P链原子、能被官能化的支链或直链C1-C6烷基链;任何氨基酸侧链;任选含有1个或2个N、S、O或P原子的4-7元杂环;或任选含有1个或2个N、O或S原子、能与另一个环稠合的5元或6元芳环;或被所述芳环取代的所述烷基链。
通常,R11表示R10NH,其中R10为R1CO或HOOC(X)x,其中R1定义同上,x为0或1,X为R1R1C,其中各R1可相同或不同,定义同上;或R10为氨基酸残基H2N(R1R1C)CO-,其中各R1可相同或不同,定义同上。
式(E)化合物为N-酰化氨基酸或聚羧酸。典型的化合物为其中R1为H和/或R12为H或乙基的那些化合物。当R11表示R10NH时,所述化合物通常为二肽,这样R10为天然氨基酸如甘氨酸的酰基。典型优选的这种化合物包括Gly-Asp(C18)、环型Gly-Asp(C19)、β-Gly-Asp(C20)、Gly-Glu(C21)和Z-Gly-Glu(C22)。其它典型的化合物包括其中R10为乙酰基或苯甲酰基的那些化合物,如L-天冬氨酸(C6)和L-谷氨酸(C7)的N-乙酰化衍生物,即R10为乙酰基,以及谷氨酸(C15和Is90)的N-苯甲酰化衍生物,即R10为苯甲酰基。其它典型的化合物包括其中R11为-NHOH的那些化合物,如2-(羟基氨基)-戊二酸二乙酯(Is51为该化合物的外消旋型),以及其中R11为OH的化合物,例如2-羟基戊二酸(Is57)。当R11为HOOC(X)x时,X特别为CH2或CHOH。所述化合物通常为柠檬酸(C12)、丙三羧酸(C13)和琥珀酸以及乙烷三羧酸的三甲酯(Is72)。
属于酸的化合物可以盐如钠盐的形式存在。
治疗时,所述化合物可与其它任何活性物质一起使用,例如在抗肿瘤治疗中,可使用另一抗肿瘤化合物或疗法,如放射疗法或化学疗法。
通常,调节剂提供为分离和/或纯化形式,即基本上纯的形式提供。这可以包括组合物形式,其中调节剂为至少约98%的活性成分,更优选至少约95%,还更优选至少约98%的活性成分。不过,任何这样的组合物可包括惰性载体材料或其它药学上和生理上可接受的赋形剂,如活性药物的正确给药、释放和/或稳定化所需要的那些载体或赋形剂。如下所述:本发明组合物除包含公开的调节剂化合物外,还包含一种或多种具体有治疗用途的其它分子,如抗肿瘤药。
一般来说,它们采取组合物的形式,其中化合物与药学上可接受的载体或稀释剂混合。所述载体可以是液体,例如盐水、乙醇、甘油及它们的混合物,或者是固体,例如片剂形式,或半固体形式,如配制成贮库制剂的凝胶剂,或在透皮给药媒介中如透皮贴剂。调节剂化合物或包含前者的组合物可配制成包衣移植(stent)的包衣。
本发明还公开了一种治疗方法,所述方法包括给予患者如上定义的化合物。这样的治疗的示例性目的在本文另处讨论。
这样的方法或用途的治疗/预防目的可以是通过调节,例如破坏或干扰HIFα的羟基化(可发生于例如脯氨酸402,564或其它脯氨基残基)来调节细胞中的HIFα水平。HIFα的羟基化促进pVHL结合,如上所述会导致HIFα的泛素依赖性蛋白酶解。
治疗/预防目的可能与以下病症的治疗有关:HIF水平或活性降低、亚适水平或增加而导致的病症,以及HIF水平或活性的改变会对其有利的病症。如:(i)局部缺血病症,例如器官局部缺血,包括冠状动脉、脑血管和周围血管供血不足。可按两种方法实施治疗:在已确定组织损伤后实施,如心肌梗塞(目的是限制组织损伤);预防性地防止或改善局部缺血,例如在治疗绞痛中对冠状侧支的促进作用。
(ii)伤口愈合和器官再生。
(iii)自体移植、异体移植和异种移植。
(iv)系统血压。
(v)癌症;HIFα在肿瘤细胞中通常被上调,对肿瘤生长和血管生成具有重要作用。
(vi)炎症疾病。
(vii)肺动脉血压,神经变性疾病。
(vii)代谢疾病,如糖尿病。
可通过不同方式在人体、器官或一组细胞中对HIF脯氨酰基羟化酶活性进行调节,以获得以下治疗效果:
(a)非细胞自主型:HIF系统是细胞用来影响向其它细胞发出信号的物质的产生。然后所述信号在以下两处产生作用:(i)远处作用(例如):促进红细胞HIF生成素作用于骨髓)或(ii)局部作用(血管生成生长因子提高血管在局部形成)。因此,通过改变羟化酶活性调控非细胞自主作用可用于治疗贫血和局部缺血,例如眼睛、大脑、心脏和四肢的局部缺血。许多参与生理稳态各方面的其它信号可通过或已知通过HIF活化来调节。因此,改变HIF脯氨酰羟化酶活性可用来激发或启动对治疗效果有帮助的反应,或用来防止或改善有害的反应。例如,这种方法可用来改变食欲,或全身或肺床的血压。
(b)细胞自主型:HIF系统也被细胞用来调节细胞代谢,以及有关分化、增殖和凋亡的决定。因此调控HIF系统可用来改变细胞的活力和行为。细胞活力的提高可通过提高HIF活化来实现,例如在局部缺血组织中。这种方法也可用来提高胰β细胞活力,以改善糖尿病,或提高帕金森氏病、运动神经元疾病或各种形式痴呆的一组或几组神经元的活力或功能。在一个不同的方法中可调控HIF信号来防止一组细胞增殖或促进细胞的死亡或分化。例如在恶性肿瘤中HIF系统的瞬时活化可用来促进大量肿瘤细胞死亡。
药用组合物
因此,本发明进一步的多方面提供药用组合物、药剂、药物或者用于这类目的的其它组合物,所述组合物包含一种或多种式(E)化合物或其衍生物;这类组合物在医疗方法中的应用,这种方法包括将这种组合物给予患者,以便例如治疗(可包括预防性治疗)上述医学病症;这种作用物化合物或物质在制备组合物、药剂或药物中的应用,所述组合物、药剂或药物用于任何上述目的,例如治疗本文所述病症;制备药用组合物的方法,该方法包括将这种作用物、化合物或物质与药用赋形剂、溶媒或载体以及任选其它成分进行混合。
所述作用物可用作唯一活性剂或与另外一种或任何一种其它活性物质(用抗肿瘤疗法举例来说,即为另一种抗肿瘤化合物或疗法,例如放疗或化疗)联合使用。
用于本发明医学治疗方法的作用物的使用量优选“预防有效量”或“治疗有效量”(不过根据情况,预防可以考虑为治疗),所述用量足以对不同个体产生有益作用。实际使用量、用药频率和疗程取决于所治疗病症的性质和严重程度。处方治疗,例如决定剂量等,属于普通执业医师和其它医疗医生的普通技能。
一种作用物或组合物可以单独使用或与其它治疗联合使用,根据所治疗的病症(例如上述病症)同时或序贯应用。
本发明药用组合物和按照本发明使用的药用组合物除了活性成分之外,还可包含药用赋形剂、载体、缓冲剂、稳定剂或本领域技术人员周知的其它物质。这种物质应当是无毒的,而且不应当干扰所述活性成分的疗效。载体或其它物质的确切性质取决于给药途径,给药途径可以为口服或注射,例如皮下或静脉注射。组合物通常是无菌的。
口服应用的药用组合物可以为片剂、胶囊剂、散剂或液体制剂。片剂可以包含固体载体(例如明胶)或佐剂。液体药用组合物一般含有液体载体,例如水、石油、动物或植物油、矿物油或合成油。可以包含生理盐水、葡萄糖或其它糖溶液或二元醇(例如乙二醇、丙二醇或聚乙二醇)。
对于静脉、皮内或皮下注射、或者病变部位注射而言,活性成分为胃肠外可接受的水溶液,水溶液无致热原而且具有合适的pH、等渗性和稳定性。本领域相关技术人员能够使用例如等渗溶媒(例如氯化钠注射液、Ringer氏注射液、乳酸盐林格氏注射液)制备合适的溶液。根据需要,可以包含防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其它添加剂。
脂质体、尤其是阳离子脂质体可以以载体制剂使用。上述技术和方案的实例参见Remington’s Pharmaceutical Sciences,16th edition,Osol,A.(ed),1980。
所述物质或组合物可以以局限化方式给药到特定部位,或者以某种方式给药,而这种方式针对特定的细胞或组织,例如使用动脉内stent型给药。
靶向疗法可以用来将活性物质更特异地给予某些类型的细胞,其方法是使用靶向系统,例如抗体或细胞特异性配体。出于不同的原因,可能需要靶向给药,例如如果所述作用物具有不可接受的毒性时,或者如果需要使用非常高的剂量,或者如果作用物不能进入靶细胞。
下列实施例进一步说明本发明。
实施例1
使用捕获试验体外筛选改善HIF的潜在抑制剂。表达HIF-1α残基549-582的Gal/HIF-1α/VP16融合蛋白用IVTT(参见英国申请号0118952.1)制得,其用作这种试验中的底物。未标记的底物用珠子纯化,洗涤后等分,等份在存在RCC4细胞提取物下与100μM FeCl2和2mM潜在抑制剂进行温育。如所示,抑制剂溶于DMSO或Tris。还设置了没有抑制剂但是加入等量DMSO或Tris的对照。洗涤后,测试珠子与35-S标记的pVHL IVTT相互作用的能力。细胞提取物中存在的HIF羟化酶对融合蛋白的羟化产生了捕获标记pVHL的能力,然后可以测量结合融合蛋白的标记蛋白量,确定相对HIF羟化酶活性。图1-3图示相对于没有抑制剂(DMSO/Tris对照)测得的HIF羟化酶活性时,存在特定抑制剂的HIF羟化酶活性。
Claims (6)
1.一种以下式(E)的化合物或其盐在制备用于治疗贫血的药物中的用途:
其中各R1可相同或不同,而且为H;OH;SH;任选含有1个或多个N、S、O或P链原子的支链或直链C1-C6烷基链;任何氨基酸侧链;任选含有1个或2个N、S、O或P原子的4-7元杂环,或任选含有1个或2个N、O或S原子、可与另一个环稠合的5元或6元芳环;或被所述芳环取代的所述烷基链;
R11表示OH或R10NH,其中R10为HO、R1CO或者为氨基酸残基H2N(R1R1C)CO-,其中各R1可相同或不同而且定义同上;或R11代表HOOC(X)x,其中x为0或1,X为R1R1C,其中各R1可相同或不同而且定义同上;n为1或2;R12为H或支链或直链C1-C6烷基。
2.权利要求1的用途,其中R1为H和R12为H或乙基。
3.权利要求1或2的用途,其中R11为R10NH,R10为天然氨基酸的酰基、乙酰基或苯甲酰基。
4.权利要求1或2的用途,其中R11为HOOC(X)x,X和x定义如权利要求1所述。
5.权利要求4的用途,其中X为CH2或CHOH。
6.权利要求1或2的用途,其中R11为-NHOH或-OH。
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AU2003216857B2 (en) | 2009-06-11 |
US20070066576A1 (en) | 2007-03-22 |
US20050227948A1 (en) | 2005-10-13 |
ATE430127T1 (de) | 2009-05-15 |
AU2003216857A1 (en) | 2003-10-08 |
CN101199537A (zh) | 2008-06-18 |
CA2479881A1 (en) | 2003-10-02 |
GB0206711D0 (en) | 2002-05-01 |
CN101199502A (zh) | 2008-06-18 |
MXPA04009155A (es) | 2004-11-26 |
CN101199512A (zh) | 2008-06-18 |
ES2322992T3 (es) | 2009-07-03 |
CN1653040A (zh) | 2005-08-10 |
US7662854B2 (en) | 2010-02-16 |
CN101199501A (zh) | 2008-06-18 |
CN101199503A (zh) | 2008-06-18 |
EP2065366A2 (en) | 2009-06-03 |
PL205110B1 (pl) | 2010-03-31 |
WO2003080566A2 (en) | 2003-10-02 |
WO2003080566A3 (en) | 2003-12-11 |
AU2009202216A1 (en) | 2009-06-25 |
EP2065366A3 (en) | 2009-09-02 |
JP2005520859A (ja) | 2005-07-14 |
PL371515A1 (en) | 2005-06-27 |
DE60327428D1 (de) | 2009-06-10 |
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