CN1471538A - 用于竞争性调节二肽基肽酶iv催化的肽结构 - Google Patents
用于竞争性调节二肽基肽酶iv催化的肽结构 Download PDFInfo
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- CN1471538A CN1471538A CNA028022467A CN02802246A CN1471538A CN 1471538 A CN1471538 A CN 1471538A CN A028022467 A CNA028022467 A CN A028022467A CN 02802246 A CN02802246 A CN 02802246A CN 1471538 A CN1471538 A CN 1471538A
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Abstract
本发明涉及由通式(I)代表的化合物及其药学可接受的盐。所述化合物可以用于制备预防或治疗由二肽基肽酶IV活性的调节介导的病症的药物,其中所述病症优选选自葡萄糖耐量低减、糖尿病、糖尿和代谢性酸中毒。
Description
技术领域
本发明在主题内涉及二肽基肽酶IV(DP IV,同义词:DPP IV、CD26,EC3.4.14.5)和DP IV样酶和它们对促胰岛素肽抑胃多肽1-42(GIP1-42)和胰高血糖素样肽酰胺-1(GLP-17-36)和(GLP-17-37)或它们的类似物的血浆水平的生物学作用。本发明还涉及葡萄糖耐量低减、糖尿病、糖尿和代谢性酸中毒的治疗,所述治疗通过以下进行:由于使用药理学剂量的二肽基肽酶IV的三、四和五肽底物而选择性调节DP IV样酶的活性,以抑制内源肽激素的生理学翻转。
背景技术
二肽基肽酶IV(DP IV)为切割肽链的N-末端二肽的丝氨酸蛋白酶,所述肽链优选在倒数第二位含有脯氨酸残基。
DP IV样酶与DP IV是在结构上相关的酶(Blanco等人,1998),它们可能与DP IV序列具有某些序列同源性,但是即使它们结构不相关(通过趋同进化),它们也具有DP IV通过在倒数第二位的脯氨酸残基后切割而从多肽的N-末端除去二肽的底物特异性。这种酶-一方面包括DP IV、DP II,另一方面包括吸诱素(attractin)(Fukasawa等人,2001)-还能够从多肽的N-末端除去具有倒数第二位的丙氨酸(或丝氨酸或甘氨酸残基)的二肽,但通常其催化效率比脯氨酸后切割小(Yaron&Naider,1993)。它们表现出共同的特征,即在靶蛋白的Pro位置还容纳(accomotate)Ala、Ser、Thr和其它具有小疏水侧链的氨基酸如Gly或Val。水解效力等级为Pro>Ala>>Ser,Thr>>Gly、Val。虽然蛋白DPIV、DP II、FAPα(Seprase)、DP6、DP8和DP9在结构上相关并表现出高序列同源性,但吸诱素是一种特别的功能性DPIV样酶(Sedo&Malik,2001)。
在WO 01/19866、WO 02/04610、WO 02/34900和WO 02/31134中公开了其它DPIV样酶。WO 01/19866公开了一种与DPIV和成纤维细胞激活蛋白(FAP)结构和功能类似的新的人二肽基氨基肽酶(DPP8)。WO 02/04610的二肽基肽酶IV样酶在本领域中是已知的。在GENE BANK数据库中,这种酶注册为KIAA1492(2001年2月注册,2000年4月4日提交,AB040925)并在MEROPS数据库中注册。WO 02/34900公开了一种与DPIV和DPP8的氨基酸序列具有显著同源性的二肽基肽酶9(DPP9)。WO 02/31134公开了三种DPIV样酶,DPRP1、DPRP2和DPRP3。序列分析揭示,DPRP1与WO 01/19866中公开的DPP8相同,DPRP2与DPP9相同,而DPRP3与WO 02/04610公开的KIAA1492相同。
最近,已证明DP IV负责切割胰高血糖素样肽-1和抑胃肽,从而缩短GLP-1和GIP的半衰期和它们在循环中的生理反应。从血清DPIV的抑制已证明肠降血糖素的生物活性显著增加。由于肠降血糖素是胰腺胰岛素分泌的主要刺激物并对葡萄糖处理具有直接的有益作用,DP IV抑制代表用于治疗葡萄糖耐量低减和非胰岛素依赖性糖尿病(NIDDM)和相关疾病如糖尿和代谢性酸中毒的有吸引力的方法(参见DE 196 16 486和WO 97/40832)。
酶二肽基肽酶IV的底物特异性可以以下方式概述:
1.当倒数第二位残基为脯氨酸、羟脯氨酸、脱氢脯氨酸、2-哌啶
酸或丙氨酸时,二肽基肽酶IV从N-末端水解寡肽和蛋白质,
分裂出二肽单元。根据它们的Kcat/Km值的最好的底物为在P1
位具有脯氨酸残基的底物。
2.DP IV要求P1和P2残基之间的‘反式’肽键。
3.底物的N-末端氨基必须被质子化以对DP IV易感。
4.底物的P1′位的脯氨酸残基防止底物被二肽基肽酶IV水解。例
如,这种酶不释放缓激肽中的精氨酰脯氨酸。
发明内容
这些化合物是脯氨酸特异性肽酶,特别是DP IV和其它具有类似DP IV样酶活性曲线的酶(“DP IV样酶”)的底物,且可以用作DP IV和DP IV样酶的底物或拮抗剂,以通过竞争性催化而抑制内源肽激素的生理学翻转。
式(I)的化合物可以用于治疗受试者中诊断的葡萄糖耐量低减、糖尿病、糖尿、代谢性酸中毒、癌和多发性硬化。
附图说明
图1显示血管内给予10、30和100mg/kg b.w.Ile-Pro-Ile后Wistar大鼠中的血浆DP IV活性;
图2显示给予10、30和100mg/kg b.w.Ile-Pro-Ile和作为阳性对照的10mg/kg b.w.异亮氨酰噻唑烷延胡索酸盐后Wistar大鼠中的血浆DP IV活性(AUC0-20分钟);
图3显示血管内给予10、30和100mg/kg b.w.Val-Pro-Leu后Wistar大鼠中的血浆DP IV活性;
图4显示给予10、30和100mg/kg b.w.Val-Pro-Leu和作为阳性对照的10mg/kg b.w.异亮氨酰噻唑烷延胡索酸盐后Wistar大鼠中的血浆DP IV活性(AUC0-20分钟);
图5显示口服和血管内给予100mg/kg b.w.叔丁基-Gly-Pro-Ile后Wistar大鼠中的血浆DP IV活性;
图6显示口服和血管内给予100mg/kg b.w.叔丁基-Gly-Pro-Ile和作为阳性对照的10mg/kg b.w.异亮氨酰噻唑烷延胡索酸盐后Wistar大鼠中的血浆DP IV活性(AUC0-20分钟);
图7显示口服给予100mg/kg b.w.叔丁基-Gly-Pro-Ile和作为阳性对照的10mg/kg b.w.异亮氨酰噻唑烷延胡索酸盐后糖尿病Zucker大鼠中的血浆葡萄糖浓度过程;和
图8显示口服给予100mg/kg b.w.叔丁基-Gly-Pro-Ile和作为阳性对照的10mg/kg b.w.异亮氨酰噻唑烷延胡索酸盐后糖尿病Zucker大鼠在OGTT期间的葡萄糖耐量和G-AUC的改善(G-AUC0-60分钟)。
具体实施方案
更具体地说,本发明涉及下式(I)的肽:其中
A、B、C、D和E为任何氨基酸,包括蛋白原氨基酸、非蛋白原氨基酸、L-氨基酸和D-氨基酸,且其中E和/或D可以不存在或者B和/或A可以不存在,其它条件如以下详述:
关于式(I)的其它条件:
A为除D-氨基酸之外的任何氨基酸;
B为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸(acetidine-(2)-carboxylic acid)和2-哌啶酸的氨基酸;
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸和N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸,
D为任何氨基酸或不存在,且
E为任何氨基酸或不存在;
或者
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸、D-氨基酸之外的任何氨基酸;
D为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸,且
E为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸。
本发明特别地涉及式(I)的化合物,其中
A为除D-氨基酸之外的任何氨基酸;
B为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸;
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸和N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸,
D为任何氨基酸或不存在,且
E为任何氨基酸或不存在。
本发明还涉及式(I)的化合物,其中
A为除D-氨基酸之外的任何氨基酸;
B为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸,
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸、D-氨基酸之外的任何氨基酸;
D为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸,且
E为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸。
优选A为L-氨基酸;
还优选C为L-氨基酸;
还优选E为不存在;
还优选D和E不存在;
还优选A为叔丁基-Gly、Ile或Val;
特别优选A为叔丁基-Gly;
还优选B为Pro;
还优选D为Pro;
还优选C为叔丁基-Gly、Ile或Val;
更优选C为叔丁基-Gly或Val;
特别优选C为叔丁基-Gly;
特别优选的是叔丁基-Gly-Pro-Ile、叔丁基-Gly-Pro-Val、Val-Pro-叔丁基-Gly、Ile-Pro-叔丁基-Gly或叔丁基-Gly-Pro-叔丁基-Gly和它们的药学可接受的盐。
本发明的化合物可以是游离酸肽形式或C-末端酰胺肽形式。
本发明的化合物可以游离C-末端酸或以C-末端酰胺形式存在。游离酸肽或酰胺可以通过侧链修饰改变。这种侧链修饰是,例如但不限于,高丝氨酸加成、焦谷氨酸加成、二硫键形成、天冬酰胺或谷氨酰胺残基脱酰胺、甲基化、叔丁基化、叔丁氧羰基化、4-甲基苄基化、硫代茴香基化(thioanysilation)、硫代羟甲苯基化(thiocresylation)、苄氧基甲基化、4-硝基苯基化、苄氧羰基化、2-硝基苯甲酰化、2-硝基亚磺酰化、4-甲苯磺酰化、五氟苯基化、二苯基甲基化、2-氯苄氧羰基化、2,4,5-三氯苯基化、2-溴苄氧羰基化、9-芴基甲氧羰基化、三苯基甲基化、2,2,5,7,8-五甲基苯并二氢吡喃-6-磺酰化、羟基化、甲硫氨酸氧化、甲酰化、乙酰化、茴香基化、苄基化、苯甲酰化、三氟乙酰化、天冬氨酸或谷氨酸羧化、磷酰化、硫酸化、半胱氨酰化、用戊糖、脱氧己糖、己糖胺、己糖或N-乙酰己糖胺糖基化(glycolysation)、法呢基化、肉豆蔻酰化、生物素基化、棕榈酰化、硬脂酰化、香叶基香叶基化、谷胱甘肽基化、5′-腺苷基化、ADP-核糖基化、用N-羟乙酰神经氨酸、N-乙酰神经氨酸、吡哆醛磷酸、硫辛酸、4′-磷酸泛酰巯基乙胺或N-羟基琥珀酰亚胺修饰。
在式(I)的化合物中,根据标准命名法,氨基酸A、B、C、D和E分别以常规方式通过酰胺键与相邻氨基酸连接,从而使氨基酸的氨基末端(N-末端)在左边,而氨基酸的羧基末端在右边。
可以用于本发明的氨基酸的实例为L和D-氨基酸、N-甲基-氨基酸;allo-和threo-形式的Ile和Thr,例如它们可以是α-、β-或ω-氨基酸,其中优选α-氨基酸。
氨基酸的实例为:天冬氨酸(Asp)、谷氨酸(Glu)、精氨酸(Arg)、赖氨酸(Lys)、组氨酸(His)、甘氨酸(Gly)、丝氨酸(Ser)和半胱氨酸(Cys)、苏氨酸(Thr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、酪氨酸(Tyr)、丙氨酸(Ala)、脯氨酸(Pro)、缬氨酸(Val)、异亮氨酸(Ile)、亮氨酸(Leu)、甲硫氨酸(Met)、苯丙氨酸(Phe)、色氨酸(Trp)、羟脯氨酸(Hyp)、β-丙氨酸(β-Ala)、2-氨基辛酸(Aoa)、氮杂环丁烷-(2)-羧酸(azetidine-(2)-carboxylic acid,Ace)、2-哌啶酸(Pip)、3-氨基丙酸、4-氨基丁酸等、α-氨基异丁酸(Aib)、肌氨酸(Sar)、鸟氨酸(Orn)、瓜氨酸(Cit)、高精氨酸(Har)、叔丁基丙氨酸(叔丁基-Ala)、叔丁基甘氨酸(叔丁基-Gly)、N-甲基异亮氨酸(N-MeIle)、苯基甘氨酸(Phg)、环己基丙氨酸(Cha)、正亮氨酸(Nle)、磺基丙氨酸(Cya)和甲硫氨酸亚砜(MSO)、乙酰-Lys,修饰的氨基酸如磷酰-丝氨酸(Ser(P))、苄基-丝氨酸(Ser(Bzl))和磷酰-酪氨酸(Tyr(P))、2-氨基丁酸(Abu)、氨基乙基半胱氨酸(AECys)、羧甲基半胱氨酸(Cmc)、脱氢丙氨酸(Dha)、脱氢氨基-2-丁酸(Dhb)、羧基谷氨酸(Gla)、高丝氨酸(Hse)、羟基赖氨酸(Hyl)、顺式羟脯氨酸(cisHyp)、反式羟脯氨酸(transHyp)、异缬氨酸(Iva)、焦谷氨酸(Pyr)、正缬氨酸(Nva)、2-氨基苯甲酸(2-Abz)、3-氨基苯甲酸(3-Abz)、4-氨基苯甲酸(4-Abz)、4-(氨基甲基)苯甲酸(Amb)、4-(氨基甲基)环己烷羧酸(4-Amc)、青霉胺(Pen)、2-氨基-4-氰基丁酸(Cba)、环烷烃羧酸。
ω-氨基酸的实例为,例如:5-Ara(氨基戊酸)、6-Ahx(氨基己酸)、8-Aoc(氨基辛酸)、9-Anc(氨基壬酸)、10-Adc(氨基癸酸)、11-Aun(氨基十一酸)、12-Ado(氨基十二酸)。
其它氨基酸为:2,3-二氢化茚基甘氨酸(Igl)、二氢吲哚-2-羧酸(Idc)、八氢吲哚-2-羧酸(Oic)、二氨基丙酸(Dpr)、二氨基丁酸(Dbu)、萘基丙氨酸(1-Nal)、(2-Nal)、4-氨基苯丙氨酸(Phe(4-NH2))、4-苯甲酰苯丙氨酸(Bpa)、二苯丙氨酸(Dip)、4-溴苯丙氨酸(Phe(4-Br))、2-氯苯丙氨酸(Phe(2-Cl))、3-氯苯丙氨酸(Phe(3-Cl))、4-氯苯丙氨酸(Phe(4-Cl))、3,4-氯苯丙氨酸(Phe(3,4-Cl2))、3-氟苯丙氨酸(Phe(3-F))、4-氟苯丙氨酸(Phe(4-F))、3,4-氟苯丙氨酸(Phe(3,4-F2))、五氟苯丙氨酸(Phe(F5))、4-胍基苯丙氨酸(Phe(4-胍基))、高苯丙氨酸(hPhe)、3-jodo苯丙氨酸(Phe(3-J))、4-iodo苯丙氨酸(Phe(4-J))、4-甲基苯丙氨酸(Phe(4-Me))、4-硝基苯丙氨酸(Phe-4-NO2))、联苯基丙氨酸(Bip)、4-膦酰基甲基苯丙氨酸(Pmp)、环己基甘氨酸(Ghg)、3-吡啶基丙氨酸(3-Pal)、4-吡啶基丙氨酸(4-Pal)、3,4-脱氢脯氨酸(A-Pro)、4-酮脯氨酸(Pro(4-keto))、硫代脯氨酸(Thz)、六氢异烟酸(isonipecotic acid)(lnp)、1,2,3,4-四氢异喹啉-3-羧酸(Tic)、炔丙基甘氨酸(Pra)、6-羟基正亮氨酸(NU(6-OH))、高酪氨酸(hTyr)、3-jodo酪氨酸(Tyr(3-J))、3,5-二jodo酪氨酸(Tyr(3,5-J2))、d-甲基-酪氨酸(Tyr(Me))、3-NO2-酪氨酸(Tyr(3-NO2))、磷酸酪氨酸(Tyr(PO3H2))、烷基甘氨酸、1-氨基茚满-1-羧酸、2-氨基茚满-2-羧酸(Aic)、4-氨基-甲基吡咯-2-羧酸(Py)、4-氨基-吡咯烷-2-羧酸(Abpc)、2-氨基四氢萘-2-羧酸(Atc)、二氨基乙酸(Gly(NH2))、二氨基丁酸(Dab)、1,3-二氢-2H-isoinole-羧酸(Disc)、高环己基丙氨酸(hCha)、高苯丙氨酸(hPhe或Hof)、反式-3-苯基-氮杂环丁烷-2-羧酸、4-苯基-吡咯烷-2-羧酸、5-苯基-吡咯烷-2-羧酸、3-吡啶基丙氨酸(3-Pya)、4-吡啶基丙氨酸(4-Pya)、苯乙烯基丙氨酸、四氢异喹啉-1-羧酸(Tiq)、1,2,3,4-四氢去甲哈尔满(norharmane)-3-羧酸(Tpi)、β-(2-thienryl)-丙氨酸(Tha)。
编码在遗传密码中的氨基酸的氨基酸置换也可以包括在本发明范围内的肽化合物中。
本发明还涉及包含至少一种本发明的化合物和药学可接受的载体和/或稀释剂的药物组合物。
这种药物组合物可以通过将至少一种本发明的化合物和药学可接受的载体和/或稀释剂混合而制备。
根据本发明的化合物和组合物可以用于制备预防或治疗由二肽基肽酶IV活性的调节介导的药物。
例如,这些病症选自葡萄糖耐量低减、糖尿病、糖尿、代谢性酸中毒、癌症和多发性硬化。
本文所用的术语“受试者”指动物,优选哺乳动物,最优选人,它是治疗、观察或试验的对象。
本文所用的术语“治疗有效量”意指研究者、兽医、医生或其它临床医生寻求的在组织系统、动物或人中引起生物或药物反应,包括缓解在治疗的疾病或病症的症状的活性化合物或药学试剂的量。
本文所用的术语“组合物”意指包括含有治疗有效量的本发明的化合物的产品,和任何直接或间接地由所要求的化合物的组合得到的产品。
本发明的化合物还可以药学可接受的盐的形式存在。药学可接受的盐一般采取其中氨基酸碱基侧链被无机或有机酸质子化的形式。代表性的有机或无机酸包括例如盐酸、氢溴酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、延胡索酸、苹果酸、酒石酸、柠檬酸、苯甲酸、苦杏仁酸、甲磺酸、羟基乙磺酸、苯磺酸、草酸、双羟萘酸、2-萘磺酸、对甲苯磺酸、环己烷氨基磺酸、水杨酸、己糖酸或三氟乙酸。
本发明在其范围内还包括本发明的化合物的前药。一般而言,这种前药是这些化合物的可以在体内容易地转化为期望的治疗活性化合物的官能衍生物。因此在这些情况下,本发明的用途包括用一种或多种所要求的化合物的前药形式治疗所述的多种疾病,所述前药在给予受试者后在体内转化为上述化合物。例如在以下文献中描述了用于选择和制备适宜的前药衍生物的常规方法:“Design of Prodrugs”,ed.H.Bundgaard,Elsevier,1985和专利申请DE 198 28 113和WO99/67278、DE 198 28 114和WO 99/67279,本文引用所述文献作为参考。
当根据本发明的化合物具有至少一个手性中心时,它们可以相应地以消旋体存在。当这些化合物具有两个或更多个手性中心时,它们还可以非对映体存在。应该理解,所有这些异构体及其混合物都包括在本发明的范围内。而且,所述化合物的某些结晶形式可以多晶型物存在并同样包括在本发明内。此外,某些所述化合物可以与水(即水合物)或常规有机溶剂形成溶剂化物,而这些溶剂化物也包括在本发明的范围内。
在本申请人的发明之前,已知的体外脯氨酸特异性丝氨酸蛋白酶二肽基肽酶IV的肽底物为三肽Diprotin A(Ile-Pro-Ile)、Diprotin B(Val-Pro-Leu)和Diprotin C(Val-Pro-Ile)。这些化合物本身被排除在本发明之外。申请人已意外地发现本文公开的药理学剂量的化合物担当哺乳动物的体内二肽基肽酶IV底物,通过竞争性催化抑制内源肽激素的生理学翻转。
可以用作二肽基肽酶IV和DP IV样酶调节剂的本发明的特别优选的化合物或前药包括显示DP IV结合的Ki值,在血管内(i.v.)和/或口服(p.o.)给予Wistar大鼠后在体内有效抑制DP IV,并且在i.v.或p.o.给予fa/fa Zucker大鼠后有效改善葡萄糖耐量的化合物或前药。
本发明的调节剂可以使用固相化学,或者通过普通溶液化学,使用本领域中已知的常规方法制备。
可以根据实施例3和4中所述的方法确定式(I)的化合物用作DPIV底物以通过体内竞争性催化而抑制内源肽激素的生理学翻转的用途。因此,本发明提供预防或治疗需要其的患者的由DP IV活性的调节介导的病症的方法,所述方法包括以有效治疗该病症的量和剂量方案给予任何所述化合物或其药物组合物。此外,本发明包括式(I)的化合物用于制备预防或治疗受试者的由DP IV活性的调节介导的病症的药物的用途。所述化合物可以任何常规给药途径给予患者,所述给药途径包括但不限于静脉内、口服、皮下、肌内、皮内和肠胃外或它们的组合。优选口服给药。
本发明还提供包含一种或多种本发明的化合物和药学可接受的载体和/或稀释剂的药物组合物。
为了制备本发明的药物组合物,首先根据常规药物复合技术,将作为活性成分的一种或多种式(I)的化合物或它们的盐与药物载体和/或稀释剂混合,所述载体根据给药例如口服或肠胃外给药如肌内给药所需的制剂形式而采用多种形式。在制备口服剂型的组合物中,可以使用任何常规药物介质。因此,对于液体口服制剂如混悬剂、酏剂和溶液剂,适宜的载体和添加剂可以有利地包括水、乙二醇、油、醇、食用香料、防腐剂、着色剂等;对于固体口服制剂如散剂、胶囊剂、凝胶胶囊剂(gelcap)和片剂,适宜的载体和添加剂包括淀粉、糖、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等。由于片剂和胶囊剂给药方便,因而它们代表最有利的口服单元剂型,在这种情况下使用固体药物载体。如果需要的话,片剂可以通过标准技术包糖衣或包肠溶衣。对于肠胃外给药,载体通常包含无菌水,虽然也可以包括其它成分,例如用于帮助溶解或用于保存。
也可以制备注射混悬剂,在这种情况下可以使用适宜的液体载体、助悬剂等。本文的药物组合物的每剂量单元,如片剂、胶囊剂、散剂、注射剂、一茶匙量(teaspoonful)等含有转运上述有效剂量所需量的活性成分量。本文的药物组合物的每剂量单元,如片剂、胶囊剂、散剂、注射剂、栓剂、一茶匙量等含有约0.01mg至约1000mg(优选约5至约500mg),并可以约0.01至约300mg/kg体重/天(优选1-50mg/kg/天)的剂量给药。但是,剂量可以根据患者的需要、在治疗的病症的严重程度和所用的化合物而改变。可以采用每日给药或周期后(post-periodic)给药。通常剂量由医师根据患者的特征、他的/她的病症和期望的治疗效果来调节。
优选这些组合物为诸如以下的单元剂型:片剂、丸剂、胶囊剂、散剂、颗粒剂、无菌肠胃外溶液或混悬剂、计量气雾剂或液体喷雾剂、滴剂、安瓿、自我注射器装置或栓剂;用于口、肠胃外、鼻内、舌下或直肠给药,或者用于吸入或吹入给药。或者,所述组合物可以适于一周一次或一月一次给药的形式存在;例如可以使用活性化合物的不溶性盐,如癸酸盐以提供用于肌内注射的长效制剂。对于制备固体组合物如片剂,将主要的活性成分与药物载体,例如常规片剂成分如玉米淀粉、乳糖、蔗糖、山梨醇、滑石、硬脂酸、硬脂酸镁、磷酸二钙或树胶和其它药物稀释剂如水理想地混合,以形成含有本发明的化合物或其药学可接受的盐的均匀混合物的固体处方设计前组合物。当说这些处方设计前组合物均匀时,它意指活性成分理想地均匀分散在整个组合物中,从而使组合物可以容易地再分为同等有效的剂型,如片剂、丸剂和胶囊剂。然后可以将这种固体处方设计前组合物再分成含约0.01至约1000mg,优选约5至约500mg的本发明的活性成分的上述类型的单元剂型。
可以有利地将所述新组合物的片剂或丸剂包衣或复合,以提供带来延长作用优点的剂型。例如,片剂或丸剂可以包含内部剂量和外部剂量组分,后者为在前者上的外壳的形式。两组分可以由肠溶层分开,该肠溶层用于抗胃中崩解并允许内部组分完整地进入十二指肠或延迟释放。许多材料可以用作这种肠溶层或包衣,这些材料包括具有诸如虫胶、鲸蜡醇和乙酸纤维素的材料的许多聚合酸。
可以有利地引入本发明的新组合物用于口服或注射的液体形式包括水溶液、适宜调味的糖浆、含水或油的混悬剂、用食用油如棉籽油、芝麻油、椰子油或花生油调味的乳剂,以及酏剂和类似的药物载体。用于含水混悬剂的适宜的分散剂或助悬剂包括合成和天然树胶如黄芪胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。
当用于制备本发明的化合物的方法产生立体异构体的混合物时,可以通过常规技术如制备色谱法分离这些异构体。这些化合物可以制成外消旋形式,或者可以通过对映体特异性合成或拆分而制备单独的对映体。例如,可以通过诸如以下的标准技术将所述化合物拆分成它们的组成对映体:与光学活性酸,如(-)-二对甲苯甲酰-d-酒石酸和/或(+)-二对甲苯甲酰-1-酒石酸成盐而形成非对映体对,然后分步结晶并再生游离碱。还可以通过形成非对映体酯或酰胺,然后进行色谱分离并除去手性辅剂而拆分化合物。或者,可以使用手性HPLC柱拆分化合物。
在制备本发明的化合物的任何方法的过程中,可能需要和/或期望保护相关的任何分子上的敏感性或反应性基团。这可以通过常规保护基实现,如在
Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973;和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述,本文引用这些文献作为参考。这些保护基可以在随后阶段使用本领域中已知的方法方便地除去。
本发明所述的由二肽基肽酶IV和DPIV样酶调节的病症的治疗方法还可以使用包含一种或多种本文定义的化合物和药学可接受的载体的药物组合物来完成。该药物组合物可以含有约0.01mg至1000mg,优选约5至约500mg或250mg的一种或多种所述化合物,并可以组成任何适于所选择的给药模式的剂型。载体包括必需的和惰性的药物载体,包括但不限于粘合剂、助悬剂、润滑剂、食用香料、甜味剂、防腐剂、染料和包衣。适于口服给药的组合物包括固体形式,如丸剂、片剂、囊片、胶囊剂(各自包括中等释放、定时释放和延时释放配方)、颗粒剂、散剂和液体形式如溶液剂、糖浆剂、酏剂、乳剂和混悬剂。用于肠胃外给药的形式包括无菌溶液剂、乳剂和混悬剂。
有利地,本发明的化合物可以一次日剂量给药,或者总日剂量可以每天二、三或四次的分开的剂量给药。而且,本发明的化合物可以通过局部应用适宜的鼻内载体,以鼻内形式给药,或通过本领域技术人员已知的透皮药贴给药。为了以透皮递送系统的形式给药,在整个剂量方案中剂量给药当然是连续的而不是间歇的,需要相应地改变剂量强度以获得期望的治疗效果。
例如,对于片剂或胶囊剂形式的口服给药,可以将活性药物组分与口服、无毒的药学可接受的惰性载体如乙醇、甘油、水等组合。而且,如果期望或必需的话,还可以将适宜的粘合剂、润滑剂、崩解剂和着色剂引入此混合物中。适宜的粘合剂包括但不限于淀粉、明胶、天然糖如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶如阿拉伯胶、黄芪胶或油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
液体形式适于处在调味助悬剂或分散剂如合成和天然树胶,如黄芪胶、阿拉伯胶、甲基纤维素等中。对于肠胃外给药,无菌悬浮液和溶液是期望的。当期望静脉内给药时,使用一般含有适宜防腐剂的等渗制剂。
本发明的化合物还可以脂质体递送系统,如小单室载体、大单室载体和多室载体的形式给药。可以使用本领域中良好描述的方法,由多种磷脂如胆固醇、硬脂酰胺或磷脂酰胆碱形成脂质体。
还可以通过使用抗体,最优选单克隆抗体作为单独的载体,化合物分子偶联于其,而递送本发明的化合物。本发明的化合物还可以与作为靶向药物载体的可溶性聚合物偶联。这些聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰胺酚、聚羟基乙基天冬酰胺酚或被棕榈酰残基取代的聚环氧乙烷聚赖氨酸。而且,本发明的化合物可以与一类用于实现药物控释的可生物降解的聚合物偶联,这些聚合物例如聚乙酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
在需要治疗所述疾病的任何时候,本发明的化合物可以在任何前述组合物中,并根据本领域中确立的剂量方案给药。
产品的日剂量可以在0.01-1.000mg/成人/天的宽范围内变化。对于口服给药,组合物优选以片剂形式提供,所述片剂含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250、500和1000毫克活性成分,用于根据症状调节待治疗患者的剂量。有效量的药物通常以约0.1mg/kg至约300mg/kg体重/天的剂量水平提供。优选范围为约1至约50mg/kg体重/天。这些化合物可以每天1-4次的方案给药。
最佳的给药剂量可以由本领域技术人员容易地确定,且它随所用的特定化合物、给药方式、制剂强度、由于给药方式导致的生物利用度以及疾病的推进而改变。此外,在调节剂量中一般应考虑与特定的治疗患者有关的因素,包括患者年龄、体重、饮食和给药时间。
本发明的化合物或组合物可以在饭前、饭时或饭后服用。
当在饭前服用时,可以在饭前1小时,优选30或甚至15或5分钟服用本发明的化合物或组合物。
当在饭时服用时,可以将本发明的化合物或组合物混入膳食或以上述的单独剂型服用。
当在饭后服用时,在饭后5、15或30分钟甚至1小时服用本发明的化合物和组合物。
实施例
实施例1Xaa-Pro-Yaa三肽的合成一般方法
所有的合成均在肽合成器SP650(Labortec AG)上,应用Fmoc/tBu-策略进行。保护的氨基酸购自Novabiochem或Bachem。三氟乙酸(TFA)购自Merck,三异丙基硅烷(TIS)购自Fluka。
使用20%哌啶/N,N-二甲基甲酰胺(DMF)将预填充的Fmoc-Yaa-Wang树脂(2.8g/取代水平0.57mmol/g)脱保护。在用DMF洗涤后,将2eq(1.1g)Fmoc-Pro-OH溶液溶于DMF(12ml溶剂/克树脂)中。加入2eq(1.04g)2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)和4eq(1.11ml)N,N-二异丙基乙胺(DIEA),并将其置于反应容器中。将混合物于室温下振荡20分钟。然后重复偶联循环。随后用DMF、二氯甲烷、异丙醇和乙醚洗涤,接着干燥所得的Fmoc-Pro-Ile-Wang树脂,并在偶联最后的氨基酸衍生物之前将其分成6份。
如上述除去Fmoc保护基。然后将在DMF中的0.54mmol Boc-氨基酸、0.54mmol TBTU和0.108mmol DIEA振荡20分钟。重复偶联循环。最后洗涤肽树脂并如上述干燥。
使用包含以下清除剂:TFA/H2O/三异丙基硅烷(TIS)=9.5/0.25/0.25的三氟乙酸(TFA)的混合物从树脂止切割肽,持续2.5小时。
粗品肽的收率平均为80-90%。通过HPLC在Nucleosil C18柱(7μm,250*21.20mm,100A)上纯化粗品肽,使用线性梯度0.1%TFA/H2O并以6ml/min增大0.1%TFA/乙腈的浓度(40分钟内从5%到65%)。
冻干得到纯肽,由电喷雾质谱和HPLC分析鉴定纯肽。结果
表1:化学合成后Xaa-Pro-Yaa三肽的鉴定
肽 | 质量(计算) | 质量(实验)1[M+H+] | HPLCk′2 |
2-氨基辛酸-Pro-Ile | 369.5 | 370.2 | 10.63 |
Abu-Pro-Ile | 313.4 | 314.0 | 5.7 |
Aib-Pro-Ile | 313.4 | 314.0 | 5.25 |
Aze-Pro-Ile | 311.4 | 312.4 | 5.29 |
Cha-Pro-Ile | 381.52 | 382.0 | 10.4 |
Ile-Hyp-Ile | 356.45 | 358.2 | 6.57 |
Ile-Pro-allo-Ile | 341.4 | 342.0 | 7.72 |
Ile-Pro-叔丁基-Gly | 341.47 | 342.36 | 6.93 |
Ile-Pro-Val | 327.43 | 328.5 | 6.41 |
Nle-Pro-Ile | 341.45 | 342.2 | 8.09 |
Nva-Pro-Ile | 327.43 | 328.2 | 6.82 |
Orn-Pro-Ile | 342.42 | 343.1 | 3.73 |
Phe-Pro-Ile | 375.47 | 376.2 | 8.96 |
Phg-Pro-Ile | 361.44 | 362.2 | 7.90 |
Pip-Pro-Ile | 338.56 | 340.0 | 6.50 |
Ser(Bzl)-Pro-Ile | 405.49 | 406.0 | 9.87 |
Ser(P)-Pro-Ile | 395.37 | 396.0 | 3.35 |
Ser-Pro-Ile | 315.37 | 316.3 | 5.24 |
叔丁基-Gly-Pro-D-Val | 327.4 | 328.6 | 7.27 |
叔丁基-Gly-Pro-Gly | 285.4 | 286.3 | 3.74 |
叔丁基-Gly-Pro-Ile | 341.47 | 342.1 | 7.16 |
叔丁基-Gly-Pro-Ile-酰胺 | 340.47 | 341.3 | 7.8 |
叔丁基-Gly-Pro-叔丁基-Gly | 341.24 | 342.5 | 9.09 |
叔丁基-Gly-Pro-Val | 327.4 | 328.4 | 6.32 |
Thr-Pro-Ile | 329.4 | 330.0 | 5.12 |
Tic-Pro-Ile | 387.46 | 388.0 | 8.57 |
Trp-Pro-Ile | 414.51 | 415.2 | 9.85 |
Tyr(P)-Pro-Ile | 471.47 | 472.3 | 5.14 |
Tyr-Pro-allo-Ile | 391.5 | 392.0 | 7.02 |
Val-Pro-allo-Ile | 327.4 | 328.5 | 6.51 |
Val-Pro-叔丁基-Gly | 327.4 | 328.15 | 5.98 |
Val-Pro-Val | 313.4 | 314.0 | 5.07 |
1[M+H+]采用电喷雾质谱,以阳性离子化模式测定。
2RP-HPLC条件:
柱: LiChrospher 100 RP 18(5μm),
125×4mm
检测(UV): 214nm
梯度系统: 乙腈(ACN)/H2O(0.1%TFA)在15分钟内从5%ACN至
50%,流速1ml/min
k′=(tr-t0)/t0
t0=1.16min
Ser(Bzl)和Ser(P)分别定义为苄基-丝氨酸和磷酰-丝氨酸。
Tyr(P)定义为磷酰-酪氨酸。
实施例2Xaa-Pro-Yaa三肽的IC50-和Ki-值的测定方法IC50-值的测定
将100μl抑制剂储备液与100μl缓冲液(HEPES pH7.6)和50μl底物(Gly-Pro-pNA,最终浓度为0.4mM)混合,并在30℃下预温育。通过加入20μl纯化的猪DP IV开始反应。在405nm下在10分钟内使用HTS 7000Plus平板读数器(Perkin Elmer)测定产物pNA的形成并计算斜率。最终的抑制剂浓度范围在1mM至30nM之间。
为了计算IC50-值,使用GraFit 4.0.13(Erithacus Software)。Ki-值的测定
为了测定Ki-值,以与上述相同的方式在0.05、0.1、0.2和0.4mM的最终底物浓度和覆盖IC50浓度的其它7种抑制剂浓度处测定DP IV活性。使用GraFit Software进行计算。结果
表2:Xaa-Pro-Yaa三肽的IC50-值
化合物 | IC50(mol/l) | SD(mol/l) |
Abu-Pro-Ile | 3.43e-5 | 1.75e-6 |
Aib-Pro-Ile | 无抑制 | |
AOA-Pro-Ile | 4.21e-5 | 1.26e-6 |
Aze-Pro-Ile | 7.28e-5 | 5.00e-6 |
Cha-Pro-Ile | 2.03e-5 | 2.12e-7 |
Diprotin A | 4.69e-6 | 4.11e-7 |
Diprotin B | 5.54e-5 | 5.49e-6 |
Ile-Hyp-Ile | 6.00e-3 | 6.80e-4 |
Ile-Pro-(allo)Ile | 1.54e-5 | 3.81e-7 |
Ile-Pro-叔丁基-Gly | 8.23e-5 | 3.84e-6 |
Ile-Pro-Val | 1.52e-5 | 7.68e-7 |
Nle-Pro-Ile | 2.19e-5 | 5.27e-7 |
Nva-Pro-Ile | 2.49e-5 | 8.23e-7 |
Om-Pro-Ile | 2.16e-4 | 4.44e-5 |
Phe-Pro-Ile | 6.20e-5 | 2.74e-6 |
Phg-Pro-Ile | 1.54e-4 | 1.34e-5 |
Pip-Pro-Ile | >0.100 | |
Ser(P)-Pro-Ile | 1.20e-2 | 0.0015 |
Ser(Bzl)-Pro-Ile | 6.78e-5 | 3.07e-6 |
Ser-Pro-Ile | 2.81e-4 | 4.69e-5 |
叔丁基-Gly-Pro-D-Val | 1.12e-4 | 5.62e-6 |
叔丁基-Gly-Pro-Gly | 5.63e-5 | 1.67e-6 |
叔丁基-Gly-Pro-Ile | 9.34e-6 | 9.08e-7 |
叔丁基-Gly-Pro-Ile-NH2 | 2.29e-5 | 1.13e-6 |
叔丁基-Gly-Pro-叔丁基-Gly | 2.45e-5 | 8.01e-7 |
叔丁基-Gly-Pro-Val | 1.38e-5 | 1.28e-6 |
Thr-Pro-Ile | 1.00e-4 | 4.43e-6 |
Tic-Pro-Ile | 0.0008 | 9.28e-6 |
Trp-Pro-Ile | 3.17e-4 | 1.80e-5 |
Tyr(P)-Pro-Ile | 1.77e-3 | 9.36e-4 |
Tyr-Pro-(allo)Ile | 6.41e-5 | 3.07e-6 |
Val-Pro-(allo)Ile | 1.80e-5 | 7.61e-7 |
Val-Pro-Val | 1.64e-5 | 1.22e-6 |
Ser(Bzl)和Ser(P)分别定义为苄基-丝氨酸和磷酰-丝氨酸。
Tyr(P)定义为磷酰-酪氨酸。
表3:Xaa-Pro-Yaa三肽的Ki-值
化合物 | Ki(mol/l) | SD(mol/l) |
Abu-Pro-Ile | 8.75e-6 | 1.52e-6 |
AOA-Pro-Ile | 1.26e-5 | 2.2e-6 |
Aze-Pro-Ile | 2.05e-5 | 3.77e-6 |
Cha-Pro-Ile | 5.99e-6 | 2.11e-7 |
Diprotin A | 3.45e-6 | 2.08e-7 |
Diprotin B | 2.24e-5 | 1.5e-7 |
Ile-Pro-(allo)Ile | 5.22e-6 | 2.58e-7 |
Ile-Pro-叔丁基-Gly | 1.89e-5 | 8.30e-7 |
Ile-Pro-Val | 5.25e-6 | 1.82e-8 |
NIe-Pro-Ile | 9.60e-6 | 3.18e-8 |
Nva-Pro-Ile | 6.17e-6 | 1.08e-6 |
Phe-Pro-Ile | 1.47e-5 | 3.92e-8 |
Ser(Bz)-Pro-Ile | 2.16e-5 | 1.79e-6 |
叔丁基-Gly-Pro-D-Val | 2.65e-5 | 1.63e-7 |
叔丁基-Gly-Pro-Gly | 1.51e-5 | 8.70e-7 |
叔丁基-Gly-Pro-Ile | 3.10e-6 | 1.56e-8 |
叔丁基-Gly-Pro-Ile-NH2 | 5.60e-6 | 1.24e-8 |
叔丁基-Gly-Pro-叔丁基-Gly | 1.41e-5 | 1.18e-7 |
叔丁基-Gly-Pro-Val | 3.10e-6 | 1.60e-7 |
Tyr-Pro-(allo)Ile | 1.82e-5 | 3.36e-8 |
Val-Pro-(allo)Ile | 9.54e-6 | 2.56e-8 |
Val-Pro-叔丁基-Gly | 1.96e-5 | 1.31e-6 |
Val-Pro-Val | 4.45e-6 | 3.78e-9 |
Ser(Bzl)和Ser(P)分别定义为苄基-丝氨酸和磷酰-丝氨酸。
Tyr(P)定义为磷酰-酪氨酸。
实施例3血管内和口服给药后Xaa-Pro-Yaa三肽在Wistar大鼠中对DP IV的血浆活性的影响研究设计动物
N=10只体重>350g的雄性Wistar大鼠(Shoe:Wist(Sho))购自Tierzucht Schnwald(Schnwalde,Germany)。饲养条件
在常规条件下,用受控的温度(22±2℃),以12/12小时光/暗循环(在06:00a.m.给光)单一笼养动物。允许其随意获取标准丸状固体食物(ssni Soest,Germany)和用HCl酸化的自来水。颈动脉和颈静脉的表征
在一周的饲养条件适应后,在常规麻醉(腹膜内注射0.25ml/kgb.w.Rompun[2%],BayerVital,Germany和0.5ml/kg b.w.Ketamin10,Atarost GmbH&Co.,Twistringen,Germany)下将导管植入Wistar大鼠的颈动脉。使动物恢复一周。每周用肝素-盐水(1001U/ml)冲洗导管三次。
如果导管功能不良,则将第二根导管插入相应大鼠的对侧颈动脉中。在外科手术恢复一周后,使动物再次用于研究。如果第二根导管功能不良,则将动物从研究中撤出。补充新的动物并以计划的顺序继续试验,所述试验在导管植入后至少5天开始。实验设计
以随机的顺序分别将测试物质血管内(动脉内)或口服给予具有完整导管功能的大鼠(各组N=3只Wistar大鼠)。作为阳性对照,血管内给予10mg/kg b.w.异亮氨酸噻唑烷*延胡索酸盐。
在过夜禁食后,在-30、-5和0分钟将100μl肝素化动脉血样收集至冰冷的Eppendorf管中(参见以下)。将测试物质新鲜溶于1.0ml盐水(0.154mol/l)并在0分钟通过饲管(15g,75mm;Fine ScienceTools,Heidelberg,Germany)口服或血管内给予。对于血管内途径,立即用30μl盐水冲洗导管并另外通过饲管口服给予1ml盐水。
然后在5、10(仅在有限数目的试验中)、20、40、60和120分钟从有知觉的不受限制的大鼠的颈动脉导管取动脉血样品,并且总是将所述动脉血样品置入填充有10μl lM柠檬酸缓冲液pH3.0的冰冷的Eppendorf管(Eppendorf Netheler-Hinz,Hamburg,Germany)中,以防止血浆DP IV活性导致的三肽的进一步水解。立即将Eppendorf管离心(12000rpm持续2分钟,Hettich Zentrifuge EBA12,Tuttlingen,Germany):在冰上保存血浆部分直至分析或在将其于-20℃下深冷直至分析。分析方法血浆DP IV活性:试验混合物由80μl试剂和20μl血浆组成。在30℃下预温育2分钟后,在390nm处,在1分钟内在相同的温度下进行黄色产物4-硝基苯胺形成的动力学测定。活性以任意单位[AU]和DP IV活性[mU/ml]表示。统计方法
计算血浆DP IV活性的绝对值、血浆DP IV活性的相对变化和最大抑制的时间和程度。数据表示包括表示曲线下面积(AUC),它用于评价在两小时的观察期间血浆DP IV活性的抑制程度。使用梯形规则计算AUC。反应性AUC具有在开始给予抑制剂的0分钟的基线数值。为了比较DP IV活性的不同初始值条件下参数的相对变化,在测试开始时设置均匀的标准化平均值(值)(参见附图和表)。
用Microsoft Excels97进行统计学评价。所有的变量均以平均值和标准偏差(SD)表示。通过斯氏t检验比较治疗组,通过配对t检验比较组内变化。认为p<0.05的双尾值是显著性的。结果在Wistar大鼠中Ile-Pro-Ile对血浆DP IV活性的影响
通过血管内途径给予Wistar大鼠递增剂量的10、30和100mg/kgb.w.的Ile-Pro-Ile(表1)。
在Ile-Pro-Ile的血管内给药后,存在由Ile-Pro-Ile导致的剂量依赖性血浆DP IV抑制的趋势。这种抑制仅在100mg/kg b.w.的剂量下是显著性的(相对于在0分钟时的DP IV活性)。参见图1,其表明由Ile-Pro-Ile导致的DP IV抑制迅速降低。在给药后20分钟二肽基肽酶IV活性的初始水平得以恢复。
参考图2,可以看出在100mg/kg b.w.的剂量下DP IV活性的曲线下面积显著性地减小(-159±40mU*min*ml-1,p<0.05)。
表4在血管内施用Ile-Pro-Ile后Wistar大鼠的血浆DP IV活性
时间 最小的 AUC(mU·min/ml)DP IV(mU/ml) 日期 -30 -5 0 5 10 20 40 60 120 最小 时间 下降 0-120 0--20FS-5 4月3日 24,4 22,6 25,8 23,6 24,2 24,3 24,3 24,8 23,6 5 2,1 -171,4 -33,7FS-2 4月2日 27,2 29,8 25,9 23,2 27,2 25,4 28,5 23,2 23,2 5 2,6 14,3 -16,4FS-7 4月6日 19,3 19,7 20,5 20,2 20,6 20,6 19,3 18,0 20,2 5 0,3 -122,5 -2,4
平均值 23,6 24,1 24,1 22,4 24,0 23,5 24,0 22,0 22,4 5,0 1,7 -93,2 -17,5
SD 4,0 5,2 3,1 1,9 3,3 2,5 4,6 3,6 1,9 0,0 1,2 96,2 15,7标准.平均 24,6 25,0 25,0 23,3 24,9 24,4 25,0 22,9 22,9
时间 最小的 AUC(mU·min/ml)DP IV(mU/ml) 日期 -30 -5 0 5 10 20 40 60 120 最小 时间 下降 0-120 0-20FS-2 4月10日 32,0 34,6 30,3 25,0 32,9 25,4 31,1 34,2 25,0 5 5,3 50,4 -32,9FS-9 4月11日 25,0 25,0 28,1 15,4 28,5 25,0 28,1 25,0 15,4 5 12,7 -273,0 -123,9FS-14 4月26日 16,7 17,1 15,4 10,1 15,4 15,8 12,7 14,9 10,1 5 5,3 -162,3 -52,6
平均值 24,6 25,6 24,6 16,8 25,6 22,1 24,0 24,7 16,8 5,0 7,7 -128,3 -69,8
SD 7,7 8,8 8,1 7,6 9,1 5,4 9,9 9,7 7,6 0,0 4,3 164,4 47,9标准.平均 25,0 26,0 25,0 17,3 26,0 22,5 24,4 25,1 17,3
时间 最小的 AUC(mU·min/ml)DP IV(mU/ml) 日期 -30 -5 0 5 10 20 40 60 120 最小 时间 下降 0-120 0-20FS-13 4月23日 16,7 19,3 21,1 5,3 6,6 19,7 21,1 19,7 21,9 5,3 5 15,8 -233,6 -194,1FS-10 4月30日 21,9 20,6 21,1 4,8 8,8 22,4 22,8 20,2 20,0 4,8 5 16,2 -185,1 -166,7FS-14 4月30日 15,4 14,9 14,9 5,3 6,1 14,5 14,5 18,0 15,8 5,3 5 9,6 9,7 -116,2
平均值 18,0 18,3 19,0 5,1 7,2 18,9 19,4 19,3 19,2 5,1 5,0 13,9 -133,0 -159,0
SD 3,5 3,0 3,5 0,3 1,4 4,0 4,4 1,2 3,1 0,3 0,0 3,7 134,4 39,5标准.平均 24,0 24,3 25,0 11,1 13,2 24,9 25,4 25,3 25,2 11,1
。 。 * *+ *+在Wistar大鼠中Val-Pro-Leu对血浆DP IV活性的影响
血管内给予10和30mg/kg b.w.的Val-Pro-Leu后可见血浆DP IV活性降低的趋势(图3)。在给予10mg/kg b.w.后,最低血浆活性是5分钟时的26.2±8.0mU/ml(NS),而在给予30mg/kg后为21.8±9.8(NS)。这还反映在给予10mg/kg b.w.Val-Pro-Leu(NS)后的-34±6mUminml-1的低DP IV-AUC0-20min和给予30mg/kg b.w.Val-Pro-Leu(NS)后的-10±10mUminml-1。
参照图4,在血管内给药后100mg/kg b.w.降低5分钟时的血浆DP IV活性(10.4±3.2mU/ml;p<0.05vs.0分钟),因此DP IV-AUC0-20min轻微降低(-54±54mUminml-1;NS)。
血浆DP IV的抑制总是终止于给药后20分钟。
表5血管内施用Val-Pro-Leu后Wistar大鼠的血浆DP IV活性时间 最小的 AUC(mU·min/ml)DP IV(mU/ml)日期 -30 5 0 5 10 20 40 60 120 最小 时间 下降 0-120 0-20FS-5 4月3日 24,4 22,6 25,8 23,6 24,2 24,3 24,3 24,8 23,6 5 2,1 -171,4 -33,7FS-2 4月2日 27,2 29,8 25,9 23,2 27,2 25,4 28,5 23,2 23,2 5 2,6 14,3 -16,4FS-7 4月6日 19,3 19,7 20,5 20,2 20,6 20,6 19,3 18,0 20,2 5 0,3 -122,5 -2,4
平均值 23,6 24,1 24,1 22.4 24.0 23.5 24.0 22.0 22.4 5.0 1.7 -93.2 -17.5
SD 4,0 5,2 3,1 1,9 3,3 2,5 4,6 3,6 1,9 0,0 1,2 96,2 15,7标准.平均 24,6 25,0 25,0 23,3 24,9 24,4 25,0 22,9 22,9
时间 最小的 AUC(mU·min/ml)DP IV(mU/ml)日期 -30 -5 0 5 10 20 40 60 120 最小 时间 下降 0-120 0-20FS-2 4月10日 32,0 34,6 30,3 25,0 32,9 25,4 31,1 34,2 25,0 5 5,3 50,4 -32,9FS-9 4月11日 25,0 25,0 28,1 15,4 28,5 25,0 28,1 25,0 15,4 5 12,7 -273,0 -123,9FS-14 4月26日 16,7 17,1 15,4 10,1 15,4 15,8 12,7 14,9 10,1 5 5,3 -162,3 -52,6
平均值 24,6 25,6 24,6 16,8 25,6 22,1 24,0 24,7 16,8 5,0 7,7 -128,3 -69,8
SD 7,7 8,8 8,1 7,6 9,1 5,4 9,9 9,7 7,6 0,0 4,3 164,4 47,9标准.平均 25,0 26,0 25,0 17,3 26,0 22,5 24,4 25,1 17,3
时间 最小的 AUC(mU·min/ml)DP IV(mU/ml)日期 -30 -5 0 5 10 20 40 60 120 最小 时间 下降 0-120 0-20FS-13 4月23日 16,7 19,3 21,1 5,3 6,6 19,7 21,1 19,7 21,9 5,3 5 15,8 -233,6 -194,1FS-10 4月30日 21,9 20,6 21,1 4,8 8,8 22,4 22,8 20,2 20,0 4,8 5 16,2 -185,1 -166,7FS-14 4月30日 15,4 14,9 14,9 5,3 6,1 14,5 14,5 18,0 15,8 5,3 5 9,6 19,7 -116,2
平均值 18,0 18,3 19,0 5,1 7,2 18,9 19,4 19,3 19,2 5,1 5,0 13,9 -133,0 -159,0
SD 3,5 3,0 3,5 0,3 1,4 4,0 4,4 1,2 3,1 0,3 0,0 3,7 134,4 39,5标准平均 24,0 24,3 25,0 11,1 13,2 24,9 25,4 25,3 25,2 11,1
。 。 * *+ *+
化合物Ile-Pro-Ile和Val-Pro-Leu在以相对高的剂量(100mg/kgb.w.)血管内给药后抑制Wistar大鼠中的血浆DP IV活性。Ile-Pro-Ile在血管内给药后似乎是剂量依赖性抑制DP IV。在Wistar大鼠中叔丁基Gly-Pro-Ile对血浆DP IV活性的影响
口服和血管内给予100mg/kg b.w.叔丁基-Gly-Pro-Ile。参照图5,叔丁基-Gly-Pro-Ile在口服给予时确实在40分钟的时间内缓慢降低血浆DP IV。血管内给予100mg/kg b.w.导致在5分钟时快速降至10mU/ml以下(p<0.05)。其后发现恢复(p<0.05,5分钟vs.40分钟)。DP IV-AUC0-120min在血管内给药(-617±234mUminml-1)后比口服给药(-336±162mUminml-1)后降低更多。
DP IV-
时间 AUCDP IV(mU/m1) -30 -5 0 2,5 5 7,5 10 15 20 40 60 120 最小 下降 (AU·分)53-4 21,93 23,68 19,74 20,61 23,68 21,05 21,93 29,39 25,00 21,49 21,93 16,23 16,23 6,58 155,253-7 26,75 37,28 23,68 9,21 13,16 12,28 25,88 15,79 10,97 8,77 14,47 23,25 8,77 23,25 -961,153-10 18,86 18,86 17,11 21,93 20,61 18,42 17,11 17,98 27,63 21,93 23,25 17,11 1,75 651,3
平均值
SD 3,98 9,55 3,31 6,99 5,41 4,50 4,39 7,30 9,92 9,62 4,30 4,05 4,58 11,28 825,8标准平均值 22,34 26,43 20,00 17,08 18,98 17,08 21,46 20,88 17,81 19,12 19,27 20,73 17,08
DP IV-
时间 AUCDP IV(mU/ml) -30 -5 0 2,5 5 7,5 10 15 20 40 60 120 显小 下降 (AU·分)53-4 19,30 21,05 19,74 15,35 15,35 17,11 17,11 14,47 15,35 14,91 15,79 17,11 14,47 5,70 -452,953-7 24,12 25,88 33,77 27,63 25,00 27,63 20,18 18,42 25,44 23,68 22,37 25,88 18,42 6,58 -1179,353-10 17,11 16,67 17,98 14,04 16,23 18,42 14,47 13,60 15,35 15,35 13,60 15,35 13,60 32,9 -388,2
平均值
SD 3,59 4,61 8,65 7,50 5,34 5,74 2,85 2,57 5,82 4,94 4,57 5,64 2,57 1,70 439,3标准平均值 16,35 17,37 20,00 15,18 15,03 17,22 13,42 11,67 14,88 14,15 13,42 15,61 11,67
表8显示所选择的Xaa-Pro-Yaa三肽在口服和血管内给予Wistar大鼠后测试它们的DPIV和DPIV样酶活性抑制能力的结果。表8结果-在将Xaa-Pro-Yaa三肽给予Wistar大鼠后tmax时的DPIV
抑制
实施例4Xaa-Pro-Yaa三肽对糖尿病Zucker大鼠的葡萄糖耐量的影响研究设计动物
结构 | 剂量(mg/kg) | i.v.(%) | p.o.(%) |
Diprotin A(Ile-Pro-Ile) | 100 | 73 | 无抑制 |
Diprotin B(Val-Pro-Leu) | 100 | 50 | 无抑制 |
Tyr(P)-Pro-Ile | 100 | 37 | 无抑制 |
叔丁基-Gly-Pro-Ile | 100 | 71 | 28 |
叔丁基-Gly-Pro-Val | 100 | 72 | 25 |
N=30只平均11周龄(5-12周),平均体重350g(150-400g)的雄性Zucker大鼠购自Charles River(Sulzfeld,Germany)。将它们饲养>12周直至所有肥胖Zucker大鼠均具有明显的糖尿病特征。饲养条件
在常规条件下,用受控的温度(22±2℃),以12/12小时光/暗循环(在06:00a.m.给光)单一笼养大鼠。允许其随意获取标准丸状固体食物(ssnif Soest,Germany)和用HCl酸化的自来水。颈动脉表征
为进行测试,良好地准备适应饲养条件的17-24周龄的肥胖Zucker大鼠。在常规麻醉(腹膜内注射0.25ml/kg b.w.Rompun[20%],BayerVital,Germany和0.5ml/kg b.w.Ketamin 10,Atarost GmbH&Co.,Twistringen,Germany)下将导管植入肥胖Zucker大鼠的颈动脉中。使动物恢复一周。每周用肝素-盐水(100IU/ml)冲洗导管三次。
如果导管功能不良,则将第二根导管插入相应的大鼠的对侧颈动脉中。在外科手术恢复一周后,使动物再次用于研究。如果第二根导管功能不良,则将动物从研究中撤出。补充新的动物并以计划的顺序继续试验,所述试验起始于导管植入后至少7天。实验设计
以随机的顺序分别给予具有完整导管功能的肥胖Zucker大鼠安慰剂(1ml盐水,0.154mol/l;N=9只动物,作为对照),一种均匀剂量的异亮氨酰噻唑烷*延胡索酸盐(10mg/kg b.w.,溶于1ml盐水;N=6只动物)作为阳性对照,或100mg/kg b.w.溶于1ml盐水的测试物质(每测试组N=6只动物)。
在过夜禁食后,在-10分钟分别通过饲管(15G,75mm;FineScience Tools,Heidelberg,Germany)口服给予肥胖Zucker大鼠安慰剂、阳性对照和测试物质。在±0分钟用2g/kg b.w.葡萄糖以40%溶液(B.Braun Melsungen,Melsungen,Germany)进行口服葡萄糖耐量测试(OGTT)。通过第二根饲管给予葡萄糖。在-30分钟、-15分钟、0分钟和5、10、15、20、30、40、60、90和120分钟从颈动脉导管收集动脉血样至20μl玻璃毛细管中,将毛细管置于填充有1ml用于溶血的溶液的标准管中(血糖测定)。
此外,在-30min,在20、40、60和120min从有知觉的不受限制的肥胖Zucker大鼠的颈动脉导管取动脉血样,并将其置入填充有10μl柠檬酸钠缓冲液(pH3.0)的冰冷的Eppendorf管(Eppendorf-Netheler-Hinz,Hamburg,Germany)以进行血浆DP活性测定。立即将Eppendorf管离心(12000rpm,持续2分钟,HettichZentrifuge EBA 12,Tuttlingen;Germany);在冰上保存血浆部分直至分析。分析方法 血糖:使用葡萄糖氧化酶法测定葡萄糖水平(Super GGlukosemeβgert;Dr.Müller Gertebau,Freital,Germany)。
几种根据实施例4进行体内试验的三肽在口服给药后在Zucker大鼠中显著改善OGTT期间的葡萄糖耐量(参见表9和图7与8)。表9结果一给予Xaa-Pro-Yaa三肽后在Zucker大鼠中OGTT期间葡
萄糖耐量的改善
实施例5肽化合物与哺乳动物肽转运蛋白的相互作用
化合物 | 剂量(mg/kg b.w.) | 给药途径 | AUC对照(mmol*min/l) | AUC测试化合物(mmol*min/l) | 改善% |
叔丁基-Gly-Pro-Ile | 100 | p.o. | 766,2 | 653,2 | 14,8 |
Val-Pro-叔丁基-Gly | 100 | p.o. | 865,6 | 722,4 | 16,5 |
Ile-Pro-叔丁基-Gly | 100 | p.o. | 865,6 | 819,5 | 5,3 |
为了分析脯氨酰特异性蛋白酶抑制剂与哺乳动物肽转运蛋白的相互作用,使用两种试验系统。首先,用转基因酵母细胞对所有测试化合物进行竞争试验以确定来自底物结合部位的放射性标记的示踪剂二肽的剂量依赖性置换(EC50值)。然后在表达哺乳动物肽转运蛋白的非洲爪蟾(Xenopus)卵母细胞中对鉴定为具有良好亲合力的化合物进行转运电流的电生理学分析。由于功能表达水平随卵母细胞而变,在相同的卵母细胞中比较每一种测试化合物和5mM二肽甘氨酰-L-谷氨酰胺(Gly-Gln)引起的电流。因此在表10中测试化合物的电流相对于由Gly-Gln导致的电流以%IGly-Gln给出,表示为残基摄入。
表10结果-肽化合物与哺乳动物肽转运蛋白的相互作用
物质 | PEPT1EC50(mM) | PEPT1残基摄入%IG1y-Gln | PEPT2EC50(mM) | PEPT2残基摄入%IG1y-Gln |
Cha-Pro-Ile | 0,141±0,009 | 90 | 0,124±0,001 | 100 |
Tyr(P)-Pro-Ile | 0,902±0,058 | 0 | 0,390±0,017 | 0 |
Ser(P)-Pro-Ile | 4,1±1,3 | 0 | 4,9±1,09 | 0 |
叔丁基-Gly-Pro-D-Val | 11,1±2,8 | 0 | 1,5±0,24 | 0 |
叔丁基-Gly-Pro-D-Ile | 10,6±0,064 | 0 | 2,3±1,12 | 0 |
Ile-Pro-Val | 0,319±0,04 | 65 | 0,179±0,03 | 200 |
虽然前述说明书以说明性实施例教导了本发明的本质,但应该理解,本发明的实施涵盖本领域技术人员预期的所有常规改变、修改和/或修饰。
Claims (19)
1.由通式(I)代表的化合物:及其药学可接受的盐,其中
A为除D-氨基酸之外的任何氨基酸;
B为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸;
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸和N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸,
D为任何氨基酸或不存在,且
E为任何氨基酸或不存在,或者其中
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸、D-氨基酸之外的任何氨基酸;
D为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸,且
E为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸。
2.权利要求1的化合物,其中
A为除D-氨基酸之外的任何氨基酸;
B为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸;
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸和N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸,
D为任何氨基酸或不存在,且
E为任何氨基酸或不存在。
3.权利要求1的化合物,其中
A为除D-氨基酸之外的任何氨基酸;
B为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸,
C为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸、D-氨基酸之外的任何氨基酸;
D为选自Pro、Ala、Ser、Gly、Hyp、氮杂环丁烷-(2)-羧酸和2-哌啶酸的氨基酸,且
E为除Pro、Hyp、氮杂环丁烷-(2)-羧酸、2-哌啶酸、N-烷基化的氨基酸例如N-甲基缬氨酸和肌氨酸之外的任何氨基酸。
4.前述权利要求之任一项的化合物,其中A为L-氨基酸。
5.前述权利要求之任一项的化合物,其中C为L-氨基酸。
6.前述权利要求之任一项的化合物,其中E不存在。
7.前述权利要求之任一项的化合物,其中D和E不存在。
8.前述权利要求之任一项的化合物,其中A为叔丁基-Gly、Ile或Val。
9.前述权利要求之任一项的化合物,其中B为Pro。
10.前述权利要求之任一项的化合物,其中C为叔丁基-Gly、Ile或Val。
11.前述权利要求之任一项的化合物,其中D为Pro、Ala、Ser、Giy、Hyp、氮杂环丁烷-(2)-羧酸或2-哌啶酸。
12.权利要求1的化合物,即叔丁基-Gly-Pro-Ile、叔丁基-Gly-Pro-Val、Val-Pro-叔丁基-Gly、Ile-Pro-叔丁基-Gly或叔丁基-Gly-Pro-叔丁基-Gly及它们的药学可接受的盐。
13.前述权利要求之任一项的化合物,其中化合物为游离酸肽形式或C-末端酰胺肽形式。
14.权利要求13的化合物,其中游离酸肽形式或C-末端酰胺肽形式通过选自以下的侧链修饰而改变:高丝氨酸加成、焦谷氨酸加成、二硫键形成、天冬酰胺或谷氨酰胺残基脱酰胺、甲基化、叔丁基化、叔丁氧羰基化、4-甲基苄基化、硫代茴香基化、硫代羟甲苯基化、苄氧基甲基化、4-硝基苯基化、苄氧羰基化、2-硝基苯甲酰化、2-硝基亚磺酰化、4-甲苯磺酰化、五氟苯基化、二苯基甲基化、2-氯苄氧羰基化、2,4,5-三氯苯基化、2-溴苄氧羰基化、9-芴基甲氧羰基化、三苯基甲基化、2,2,5,7,8-五甲基苯并二氢吡喃-6-磺酰化、羟基化、甲硫氨酸氧化、甲酰化、乙酰化、茴香基化、苄基化、苯甲酰化、三氟乙酰化、天冬氨酸或谷氨酸羧化、磷酰化、硫酸化、半胱氨酰化、用戊糖、脱氧己糖、己糖胺、己糖或N-乙酰己糖胺糖基化、法呢基化、肉豆蔻酰化、生物素基化、棕榈酰化、硬脂酰化、香叶基香叶基化、谷胱甘肽基化、5′-腺苷基化、ADP-核糖基化、用N-羟乙酰神经氨酸、N-乙酰神经氨酸、吡哆醛磷酸、硫辛酸、4′-磷酸泛酰巯基乙胺和N-羟基琥珀酰亚胺修饰。
15.前述权利要求之任一项的化合物的前药。
16.包含至少一种权利要求1-15之任一项的化合物或前药和药学可接受的载体和/或稀释剂的药物组合物。
17.制备药物组合物的方法,所述方法包括将至少一种权利要求1-15之任一项的化合物或前药与药学可接受的载体和/或稀释剂混合。
18.根据前述权利要求1-15之任一项的化合物、前药或组合物用于制备预防或治疗由二肽基肽酶IV活性的调节介导的病症的药物的用途。
19.权利要求17的用途,其中病症选自葡萄糖耐量低减、糖尿病、糖尿和代谢性酸中毒。
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EP01114796.4 | 2001-06-27 |
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CN1471538A true CN1471538A (zh) | 2004-01-28 |
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CNA028022475A Pending CN1688599A (zh) | 2001-06-27 | 2002-06-27 | 二肽基肽酶iv抑制剂的新用途 |
CNA028022467A Pending CN1471538A (zh) | 2001-06-27 | 2002-06-27 | 用于竞争性调节二肽基肽酶iv催化的肽结构 |
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CNA028022475A Pending CN1688599A (zh) | 2001-06-27 | 2002-06-27 | 二肽基肽酶iv抑制剂的新用途 |
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EP (1) | EP1399469A2 (zh) |
JP (1) | JP2004530729A (zh) |
CN (2) | CN1688599A (zh) |
CA (1) | CA2419888A1 (zh) |
NO (1) | NO20030900L (zh) |
RU (2) | RU2003105463A (zh) |
WO (1) | WO2003002593A2 (zh) |
ZA (3) | ZA200301312B (zh) |
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-
2002
- 2002-06-27 CA CA002419888A patent/CA2419888A1/en not_active Abandoned
- 2002-06-27 EP EP02762308A patent/EP1399469A2/en not_active Withdrawn
- 2002-06-27 CN CNA028022475A patent/CN1688599A/zh active Pending
- 2002-06-27 JP JP2003508973A patent/JP2004530729A/ja active Pending
- 2002-06-27 ZA ZA200301312A patent/ZA200301312B/en unknown
- 2002-06-27 CN CNA028022467A patent/CN1471538A/zh active Pending
- 2002-06-27 RU RU2003105463/04A patent/RU2003105463A/ru not_active Application Discontinuation
- 2002-06-27 WO PCT/EP2002/007128 patent/WO2003002593A2/en active Application Filing
- 2002-06-27 ZA ZA200300833A patent/ZA200300833B/en unknown
- 2002-06-27 RU RU2003105464/15A patent/RU2299066C2/ru not_active IP Right Cessation
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2003
- 2003-01-22 ZA ZA200300595A patent/ZA200300595B/en unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105833256A (zh) * | 2012-03-09 | 2016-08-10 | 森永乳业株式会社 | 二肽基肽酶iv抑制剂 |
Also Published As
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NO20030900D0 (no) | 2003-02-26 |
RU2299066C2 (ru) | 2007-05-20 |
EP1399469A2 (en) | 2004-03-24 |
WO2003002593A2 (en) | 2003-01-09 |
CN1688599A (zh) | 2005-10-26 |
NO20030900L (no) | 2003-04-24 |
ZA200300833B (en) | 2004-02-10 |
CA2419888A1 (en) | 2003-01-09 |
JP2004530729A (ja) | 2004-10-07 |
RU2003105463A (ru) | 2004-11-27 |
ZA200300595B (en) | 2004-02-13 |
ZA200301312B (en) | 2004-03-30 |
WO2003002593A3 (en) | 2003-09-04 |
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