CN101107266A - 具有神经肽-2受体(y2r)激动剂活性的肽类 - Google Patents
具有神经肽-2受体(y2r)激动剂活性的肽类 Download PDFInfo
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- CN101107266A CN101107266A CNA2006800025981A CN200680002598A CN101107266A CN 101107266 A CN101107266 A CN 101107266A CN A2006800025981 A CNA2006800025981 A CN A2006800025981A CN 200680002598 A CN200680002598 A CN 200680002598A CN 101107266 A CN101107266 A CN 101107266A
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Abstract
本发明涉及式(I)的神经肽-2受体激动剂:Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2 (I)及其药用盐、衍生物和片段,其中所述取代基如说明书中公开的那些。这些化合物和含有它们的药物组合物有效用于治疗诸如例如肥胖症的疾病。
Description
本发明涉及式(I)的PYY3-36的截短类似物,
Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2(I)
其中X选自由下列各项组成的组:N-哌嗪-1-基-4(3H)-喹唑啉酮(quinozolinone)-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,R1是Ile,Ala,(D)Ile,N-甲基Ile,Aib,1-1Aic,2-2 Aic,Ach或Acp,R2是Lys,Ala,(D)Lys,NMelys,Nle或(Lys-Gly),
R3是Arg,Ala,(D)Arg,N-甲基Arg,Phe,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,R4是His,Ala,(D)His,N-甲基His,4-MeOApc,3-Pal或4-Pal,R5是Tyr,Ala,(D)Tyr,N-甲基Tyr,Trp,Tic,Bip,Dip,(1)Nal,(2)Nal,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,R6是Leu,Ala,(D)Leu或N-甲基Leu,R7是Asn,Ala或(D)Asn,R8是Leu,Ala,(D)Leu或N-甲基Leu,R9是Val,Ala,(D)Val或N-甲基Val,R10是Thr,Ala或N-甲基Thr,R11是Arg,(D)Arg或N-甲基Arg,R12是Gln或Ala,R13是Arg,(D)Arg或N-甲基Arg,并且R14是Tyr,(D)Tyr或N-甲基Tyr,或其药用盐。
该类似物是神经肽-2受体的激动剂并且有效用于治疗代谢病症,如,例如肥胖症。本文引用的所有文献通过参考由此特别地结合于此。
肥胖症被广泛认可为发达国家的一种严重健康问题,并且在美国已经达到蔓延状态。根据最近研究,超过50%的美国人口被认为超重,超过25%被诊断为临床肥胖并且处于心脏病、非胰岛素依赖型糖尿病(NIDDM)、高血压和某些癌症的相当大的风险中。这种蔓延对健康护理系统给出了重大的负担,因为仅在美国预计计划的肥胖症治疗费用每年超过$700亿。治疗肥胖症的策略包括减少食物摄入和增加能量消耗。
神经肽Y(NPY),36个氨基酸的肽神经递质,是神经递质/神经激素的胰腺多肽类的成员,其已经显示存在于周围和中枢神经系统两者中。NPY是已知最有效的orexogenic剂之一并且已经显示在包括人类的动物中在调节食物摄取方面发挥重要作用。
已经克隆了五种神经肽Y受体(NPY),Y1-,Y2-,Y3-,Y4,和Y5-以及Y6-亚型,其属于视紫红质样G-蛋白-偶联的、7-跨膜螺旋-跨越受体(GPCR)。NPY Y2受体(Y2R)是381个氨基酸,其抑制经由Gi的腺苷酸环化酶的激活而与其它已知的NPY受体具有低同源性。在大鼠和人Y2受体之间存在高度保守,98%氨基酸相同。
Y2R受体广泛分布在啮齿动物和人类两者的中枢神经系统内。在下丘脑中,Y2mRNA位于弓状核、视前核、和背内侧核中。在人脑中,Y2R是主要的Y受体亚型。在弓状核内,超过80%的NPY神经细胞共表达Y2RmRNA。Y2-选择性激动剂的应用已经显示减少体外NPY从下丘脑切片的释放,而Y2非肽拮抗剂BIIE0246增加NPY的释放。这些发现支持Y2R作为突触前自身受体的作用,其调节NPY释放并因此可能参与摄食的调节。(Poter,E.K.,等 Eur.J.Pharmac.267,253-262(1994))。
肽YY3-36(PYY3-36)是33个氨基酸的直链肽,具有特异的神经肽Y2(NPY2R)激动剂活性。已经证明弓状核内(IC)或腹膜内(IP)注射PYY3-36减少大鼠的摄食,并且作为慢性治疗,降低体重增加。静脉内(IV)输注(0.8pmol/kg/min)PYY3-36 90min在24小时内减少肥胖和正常人受试者中食物摄取33%。这些发现提示,PYY系统可以是用于治疗肥胖症的治疗靶标。(Bloom,S.等,Nature Vol.418,8 August 2002,P.650-654)。另外,PYY的Cys2-(D)Cys27-环化形式,其中残基5-24被长度为5-8个碳原子的亚甲基链替代,显示肠内PYY受体的激活,如穿过电压-钳位的大鼠空肠粘膜制剂的减少的电流所证明。(Krstenansky,等Peptides,Proceedings of the TwelfthAmerican Peptide Symposium.J.Smith and J.Rivier Editors,ESCOM.Leiden第136-137页)。
另外,聚(乙二醇)或聚(氧乙烯)(都称为PEG)对蛋白质的共价修饰用超氧化物歧化酶证实(Somack,R,等,(1991)Free Rad Res Commun12-13:553-562;U.S.Pat.Nos.5,283,317和5,468,478),并且对于其它类型的蛋白质,例如细胞因子(Saifer,MGP,等,(1997)Polym Preprints 38:576-577;Sherman,M R,等,(1997)J M Harris,等,(Eds.),Poly(ethylene glycol)Chemistry and Biological Applications.ACS Symposium Series 680(pp.155-169)Washington,D.C.:American Chemical Society)。
然而,存在对新的改造的PYY类似物的需要,该类似物具有显著更低的分子量,同时具有与现有的Y2R激动剂相等或更好的功效、药代动力学性质和药理学性质。还存在对PEG化的PYY类似物的需要,以便例如提高肽半衰期和降低需要该类似物的受试者中的免疫原性。
本发明的化合物还是有利的,因为它们是PYY3-36的截短形式。因此,该较短的肽不仅促进化合物的更容易的合成和纯化,而且改善和减少了制造程序和费用。此外,本发明的化合物将优选与PYY受体相互作用,并且不与同源的受体如NPYY1,Y4和Y5相互作用。不希望有的激动剂或拮抗剂副反应由此被最小化。
图1显示本发明化合物的HPLC色谱图。
图2显示本发明化合物的HPLC色谱图。
图3显示本发明化合物的MALDI-TOF。
图4显示本发明另一种化合物的HPLC色谱图。
图5显示本发明化合物的HPLC色谱图。
图6显示本发明化合物的MALDI-TOF。
图7显示在施用本发明的化合物以后对食物摄取的影响的图表。
图8显示在施用本发明的另一种化合物以后对食物摄取的影响的图表。
图9显示在施用本发明还有的另一种化合物以后对食物摄取的影响的图表。
图10显示在施用本发明的再一种化合物以后对食物摄取的影响的图表。
本文所述的所有肽序列是按照通常惯例书写的,由此N-末端氨基酸位于左边而C-末端氨基酸位于右边,除非另外指出。两个氨基酸残基之间的短线表示肽键。当氨基酸具有异构体形式时,除非另外特别指出,它表示的是L型氨基酸。为了在描述本发明中方便,使用了对于各种氨基酸的常规和非常规缩写。这些缩写对于本领域技术人员而言是熟悉的,但是为了清楚起见在以下列出:
Asp=D=天冬氨酸;Ala=A=丙氨酸;Arg=R=精氨酸;Asn=N=天冬酰胺;Gly=G=甘氨酸;Glu=E=谷氨酸;Gln=Q=谷氨酰胺;His=H=组氨酸;Ile=I=异亮氨酸;Leu=L=亮氨酸;Lys=K=赖氨酸;Met=M=蛋氨酸;Phe=F=苯丙氨酸;Pro=P=脯氨酸;Ser=S=丝氨酸;Thr=T=苏氨酸;Trp=W=色氨酸;Tyr=Y=酪氨酸;和Val=V=缬氨酸。
还为了方便,并且对于本领域技术人员容易理解的,使用下列缩写或符号来表示用于本发明的各部分、试剂等:
Pqa N-哌嗪-1-基-4-(3H)-喹唑啉酮(quanazolinone)-3-乙酸;
Cms N-(5-O-羧甲基)-5-羟色胺(seratonin);
3,4,5,F3-Phe 3,4,5-三氟苯丙氨酸;
2,3,4,5,6,F5-Phe 2,3,4,5,6-五氟苯丙氨酸;
4-MeO-Apc 4-甲氧基-1-氨基4-苯基环己烷羧酸;
3-Pal 3-吡啶基丙氨酸;
4-Pal 4-吡啶基丙氨酸;
Aib 氨基异丁酸;
1-1-Aic 1氨基-1,2-二氢化茚1-羧酸;
2-2-Aic 2氨基-1,2-二氢化茚2-羧酸;
Ach 1-氨基环己基羧酸;
Acp 1-氨基环戊基羧酸;
Fmoc 9-芴基甲氧基羰基;
Allyl 烯丙基酯;
Aloc 烯丙氧基羰基;
Mtt 4-甲基三苯甲基;
2Pip 2-苯基异丙酯;
Pmc 2,2,5,7,8-五甲基苯并二氢吡喃-6-磺酰基;
CH2Cl2 二氯甲烷;
A2O 乙酐;
CH3CN 乙腈;
DMAc 二甲基乙酰胺;
DMF 二甲基甲酰胺;
DIPEA N,N-二异丙基乙胺;
TFA 三氟乙酸;
HOBT N-羟基苯并三唑;
DIC N,N’-二异丙基碳二亚胺;
BOP 苯并三唑-1-基氧基-三-(二甲氨基)鏻-六氟磷酸盐;
HBTU 2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓-六氟磷酸盐;
NMP 1-甲基2-Pyrolidenone;
Bip 联苯基丙氨酸或4-苯基-苯丙氨酸;
Dip 二苯基丙氨酸;
Tic 1,2,3,4,-四氢异喹啉-3羧酸;
FAB-MS 快原子轰击质谱;和
ES-MS 电雾化质谱。
如本文所用,术语“烷基”是指支链或直链、环状或非环状、饱和或不饱和(例如链烯基或炔基)烃基基团,其可以是取代的或未取代的。当环状时,烷基优选为C3至C12、更优选C5至C10、更优选C5至C7。当非环状时,烷基优选为C1至C10,更优选C1至C6,更优选甲基,乙基,丙基(正-丙基或异丙基),丁基(正丁基,异丁基或叔丁基)或戊基(包括正戊基和异戊基),更优选甲基。因此,应当理解,本文所用的术语“烷基”包括烷基(支链或直链),取代的烷基(支链或直链),链烯基(支链或直链),取代的链烯基(支链或直链),炔基(支链或直链),取代的炔基(支链或直链),环烷基,取代的环烷基,环烯基,取代的环烯基,环炔基和取代的环炔基。
如本文所用,术语“低级烷基”是指支链或直链、环状或非环状、饱和或不饱和(例如链烯基或炔基)烃基基团,其中所述环状低级烷基是C5,C6或C7,并且其中所述非环状低级烷基是C1,C2,C3或C4,并且优选选自甲基,乙基,丙基(正-丙基或异丙基)或丁基(正丁基,异丁基或叔丁基)。因此,应当理解,本文所用的术语“低级烷基”包括低级烷基(支链或直链),低级链烯基(支链或直链),低级炔基(支链或直链),低级环烷基,低级环烯基和低级环炔基。
如本文所用,术语“芳基”是指取代或未取代的碳环芳族基团,如苯基或萘基,或取代或未取代的含有一个或多个、优选一个杂原子的杂芳基,如吡啶基,吡咯基,呋喃基,噻吩基,噻唑基,异噻唑基,噁唑基,异噁唑基,噁二唑基,噻二唑基,吡唑基,咪唑基,三唑基,嘧啶基,哒嗪基,吡嗪基,三嗪基,吲哚基,吲唑基,喹啉基,喹唑啉基,苯并咪唑基,苯并噻唑基,苯并异噁唑基和苯并异噻唑基。
烷基和芳基可以是取代的或未取代的。当取代时,通常有1至3个取代基存在,优选1个取代基。取代基可以包括:含碳基团如烷基,芳基,芳基烷基(例如取代和未取代的苯基,取代和未取代的苄基);卤素原子和含有卤素原子的基团如卤代烷基(例如,三氟甲基);含氧基团如醇(例如羟基,羟烷基,芳基(羟基)烷基),醚(例如,烷氧基,芳氧基,烷氧基烷基,芳氧基烷基),醛(例如甲醛),酮(例如烷基羰基,烷基羰基烷基,芳基羰基,芳基烷基羰基,芳基羰基烷基),酸(例如,羧基,羧基烷基),酸衍生物如酯(例如,烷氧基羰基,烷氧基羰基烷基,烷基羰基氧基,烷基羰基氧基烷基),酰胺(例如,氨基羰基,一-或二-烷基氨基羰基,氨基羰基烷基,一-或二-烷基氨基羰基烷基,芳基氨基羰基),氨基甲酸酯(例如烷氧基羰基氨基,芳氧羰基氨基,氨基羰基氧基,一-或二-烷基氨基羰基氧基,芳基氨基羰基氧基)和脲(例如一-或二-烷基氨基羰基氨基或芳基氨基羰基氨基);含氮基团如胺(例如氨基,一-或二-烷基氨基,氨基烷基,一-或二-烷基氨基烷基),叠氮化物,腈(例如氰基,氰基烷基),硝基;含硫基团如硫醇类(asthiols),硫醚,亚砜和砜(例如烷硫基,烷基亚磺酰基,烷基磺酰基,烷硫基烷基,烷基亚磺酰基烷基,烷基磺酰基烷基,芳硫基,芳基亚磺酰基,芳基磺酰基,芳硫基烷基,芳基亚磺酰基烷基,芳基磺酰基烷基);和含有一个或多个、优选一个杂原子的杂环基团(例如噻吩基,呋喃基,吡咯基,咪唑基,吡唑基,噻唑基,异噻唑基,噁唑基,噁二唑基,噻二唑基,吖丙啶基,氮杂环丁烷基,吡咯烷基,吡咯啉基,咪唑烷基,咪唑啉基,吡唑烷基,四氢呋喃基,吡喃基,吡喃酮基,吡啶基,吡嗪基,哒嗪基,哌啶基,六氢氮杂基,哌嗪基(peperazinyl),吗啉基,硫杂萘基(thianaphthyl),苯并呋喃基,异苯并呋喃基,吲哚基,羟吲哚基,异氮杂茚基,吲唑基,二氢吲哚基,7-氮杂吲哚基,苯并吡喃基,香豆素基,异香豆素基,喹啉基,异喹啉基,naphthridinyl,噌啉基,喹唑啉基,吡啶并吡啶基,苯并噁嗪基,喹喔啉基,色烯基,苯并二氢吡喃基,异苯并二氢吡喃基,2,3-二氮杂萘基和咔啉基(carbolinyl))。
所述低级烷基可以是取代的或未取代的,优选未取代的。当取代时,通常存在1至3个取代基,优选1个取代基。取代基包括除了烷基、芳基和芳基烷基以外的以上列出的取代基基团。
如本文所用,术语“烷氧基”是指烷基-O-并且“烷酰基”是指烷基-CO-。烷氧基取代基或含有烷氧基的取代基基团可以被一个或多个烷基取代。
如本文所用,术语“卤素”是指氟,氯,溴或碘基团,优选氟、氯或溴基团,并且更优选为氟或氯基团。
如本文所用,术语“药用盐”是指式(I)化合物的任何药用盐。盐可以由药用非毒性酸和碱制备,所述酸和碱包括无机的和有机的酸和碱。这些酸包括乙酸,苯磺酸,苯甲酸,樟脑磺酸,柠檬酸,乙磺酸(ethenesulfonic),二氯乙酸,甲酸,富马酸,葡糖酸,谷氨酸,马尿酸,氢溴酸,氢氯酸,羟乙磺酸,乳酸,马来酸,苹果酸,扁桃酸,甲磺酸,粘酸,硝酸,草酸,双羟萘酸,泛酸,磷酸,琥珀酸,硫酸,酒石酸,草酸,对-甲苯磺酸等。特别优选富马酸,氢氯酸,氢溴酸,磷酸,琥珀酸,硫酸和甲磺酸。可接受的碱盐包括碱金属(例如钠,钾),碱土金属(例如钙,镁)和铝盐。
在本发明的一个实施方案中,提供式(I)的神经肽-2受体激动剂:
Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2(I)
其中X选自由下列各项组成的组:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,R1是Ile,Ala,(D)Ile,N-甲基Ile,Aib,1-1Aic,2-2 Aic,Ach或Acp,R2是Lys,Ala,(D)Lys,NMelys,Nle或(Lys-Gly),
R3是Arg,Ala,(D)Arg,N-甲基Arg,Phe,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,R4是His,Ala,(D)His,N-甲基His,4-MeOApc,3-Pal或4-Pal,R5是Tyr,Ala,(D)Tyr,N-甲基Tyr,Trp,Tic,Bip,Dip,(1)Nal,(2)Nal,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,R6是Leu,Ala,(D)Leu或N-甲基Leu,R7是Asn,Ala或(D)Asn,
R8是Leu,Ala,(D)Leu或N-甲基Leu,R9是Val,Ala,(D)Val或N-甲基Val,
R10是Thr,Ala或N-甲基Thr,R11是Arg,(D)Arg或N-甲基Arg,R12是Gln或Ala,
R13是Arg,(D)Arg或N-甲基Arg,并且R14是Tyr,(D)Tyr或N-甲基Tyr,
或其药用盐。
在本发明的另一个实施方案中,提供了式(II)的神经肽-2受体激动剂:Y-R1-R2-X-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(II)(SEQ ID NO:1)
其中X是选自由下列各项组成的组的部分:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,R1是Ile,Ala,(D)Ile,N-甲基Ile,Aib,1-1Aic,2-2Aic,Ach或Acp,并且R2是Lys,Ala,(D)Lys,NMelys,Nle或(Lys-Gly),
或其药用盐。
在本发明的还有的另一个实施方案中,提供了式(III)的神经肽-2受体激动剂:
Y-Ile-Lys-X-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(III)(SEQ ID NO:2)
其中X选自由下列各项组成的组:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,并且Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,
或其药用盐。
优选的如上定义的神经肽-2受体激动剂是以下那些,其中X是Pqa。
其它优选的如上定义的神经肽-2受体激动剂是以下那些,其中X是Cms。优选地,Y是H或(C1-C6)烷基,更优选Y是(C1-C6)烷基部分。
优选的如上定义的神经肽-2受体激动剂是选自以下的那些:
IK-Pqa-RHYLNLVTRQRY,
Ac-IK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRARY,
IK-Pqa-RHYLNLVARQRY,
IK-Pqa-RHYLNLATRQRY,
IK-Pqa-RHYLNAVTRQRY,
IK-Pqa-RHYLALVTRQRY,
IK-Pqa-RHYANLVTRQRY,
IK-Pqa-RHALNLVTRQRY,
IK-Pqa-RAYLNLVTRQRY,
IK-Pqa-AHYLNLVTRQRY,
IA-Pqa-RHYLNLVTRQRY,
Ac-IA-Pqa-RHYLNLVTRQRY,
AK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRQR(D)Y,
IK-Pqa-RHYLNLVTRQ(D)RY,
IK-Pqa-RHYLNLVT(D)RQRY,
IK-Pqa-RHYLNL(D)VTRQRY,
IK-Pqa-RHYLN(D)LVTRQRY,
IK-Pqa-RHYL(D)NLVTRQRY,
IK-Pqa-RHY(D)LNLVTRQRY,
IK-Pqa-RH(D)YLNLVTRQRY,
IK-Pqa-R(D)HYLNLVTRQRY,
IK-Pqa-(D)RHYLNLVTRQRY,
I(D)K-Pqa-RHYLNLVTRQRY,
(D)IK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRQR(N-甲基)Y,
IK-Pqa-RHYLNLVTRQ(N-甲基)RY,
IK-Pqa-RHYLNLVT(N-甲基)RQRY,
IK-Pqa-RHYLNLV(N-甲基)TRQRY,
IK-Pqa-RHYLNL(N-甲基)VTRQRY,
IK-Pqa-RHYLN(N-甲基)LVTRQRY,
IK-Pqa-RHY(N-甲基)LNLVTRQRY,
IK-Pqa-RH(N-甲基)YLNLVTRQRY,
IK-Pqa-R(N-甲基)HYLNLVTRQRY,
IK-Pqa-(N-甲基)RHYLNLVTRQRY,
I(N-甲基)K-Pqa-RHYLNLVTRQRY,
(N-甲基)IK-Pqa-RHYLNLVTRQRY,
INle-Pqa-RHYLNLVTRQRY,
Ac-INle-Pqa-RHYLNLVTRQRY,
Ac-INle-Pqa-FHYLNLVTRQRY,
IK-Pqa-RHWLNLVTRQRY,
IK-Pqa-AHWLNLVTRQRY,
Ac-INle-Pqa-RHYLNLVTRQR(D)Y,
Ac-INle-Pqa-RHYLNLVTRQR(N-甲基)Y,
Ac-INle-Pqa-RHYLys(28)NLVAsp(32)RQRY(环Lys-Asp),
IK-Cms-RHYLNLVTRQRY,
IKG-Cms-RHYLNLVTRQRY,
Ac-INle-Cms-RHYLys(28)NLVAsp(32)RQRY(环Lys-Asp),
Ac-INle-Pqa-RHTicLNLVTRQRY,
Ac-INle-Pqa-RHBipLNLVTRQRY,
Ac-INle-Pqa-RHDipLNLVTRQRY,
Ac-INle-Pqa-RH(1)NalLNLVTRQRY,
Ac-INle-Pqa-RH(2)NalLNLVTRQRY,
Ac-INle-Pqa-RH(3.4,5三氟Phe)LNLVTRQRY,
Ac-INle-Pqa-RH(2,3.4,5,6五氟Phe)LNLVTRQRY,
Ac-INle-Pqa-R(4-MeOApc)YLNLVTRQRY,
Ac-INle-Pqa-R(3-Pal)YLNLVTRQRY,
Ac-INle-Pqa-R(4-Pal)YLNLVTRQRY,
Ac-INle-Pqa-(3,4,5三氟Phe)HYLNLVTRQRY,
Ac-INle-Pqa-(2,3,4,5,6五氟Phe)HYLNLVTRQRY,
Ac-Aib-Nle-Pqa-RHYLNLVTRQRT,
Ac1-1-Aic-Nle-Pqa-RHYLNLVTRQRT,
Ac1-1-Aic-Nle-Pqa-RHYLNLVTRQRT,
Ac-2-2Aic-Nle-Pqa-RHYLNLVTRQRT,
Ac-Ach-Nle-Pqa-RHYLNLVTRQRT,
Ac-Acp-Nle-Pqa-RHYLNLVTRQRT,
H-INle-Pqa-RHYLNLVTRQRY,
(PEG-10,000)INle-Pqa-RHYLNLVTRQRY,和
(PEG-30,000)INle-Pqa-RHYLNLVTRQRY。
更优选的如上定义的神经肽-2受体激动剂是选自由下列各项组成的组的那些:
IK-Pqa-RHYLNLVTRQRY,
Ac-IK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRQR(N-甲基)Y,
IK-Pqa-RHYLNLVTRQ(N-甲基)RY,
INle-Pqa-RHYLNLVTRQRY,
Ac-INle-Pqa-RHYLNLVTRQRY,和
(PEG-30,000)INle-Pqa-RHYLNLVTRQRY。
所有的上述神经肽-2受体激动剂单独地构成分别的优选实施方案。
在本发明的另一个实施方案中,提供了在需要其的患者中治疗肥胖症的方法,该方法具有向所述患者施用治疗有效量的式(I)的神经肽-2受体激动剂的步骤:
Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2(I)
其中X选自由下列各项组成的组:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,R1是Ile,Ala,(D)Ile,N-甲基Ile,Aib,1-1Aic,2-2Aic,Ach或Acp,R2是Lys,Ala,(D)Lys,NMelys,Nle或(Lys-Gly),R3是Arg,Ala,(D)Arg,N-甲基Arg,Phe,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,R4是His,Ala,(D)His,N-甲基His,4-MeOApc,3-Pal或4-Pal,
R5是Tyr,Ala,(D)Tyr,N-甲基Tyr,Trp,Tic,Bip,Dip,(1)Nal,(2)Nal,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,R6是Leu,Ala,(D)Leu或N-甲基Leu,
R7是Asn,Ala或(D)Asn,R8是Leu,Ala,(D)Leu或N-甲基Leu,R9是Val,Ala,(D)Val或N-甲基Val,R10是Thr,Ala或N-甲基Thr,R11是Arg,(D)Arg或N-甲基Arg,R12是Gln或Ala,R13是Arg,(D)Arg或N-甲基Arg,并且R14是Tyr,(D)Tyr或N-甲基Tyr,
或其药用盐。
优选的是如上所述的方法,其中将所述神经肽-2受体激动剂施用给所述患者,每三天一次。优选地,将所述神经肽-2受体激动剂每周一次施用给所述患者。
优选的是如上所述的方法,其中将所述神经肽-2受体激动剂通过以下方式施用给所述患者:口服,鼻内,静脉内,皮下,肠胃外,透皮,腹膜内或直肠。优选地,将所述神经肽-2受体激动剂鼻内施用。还优选的是将所述神经肽-2受体激动剂皮下施用。
在优选的如上所述的方法中,所述神经肽-2受体激动剂的施用剂量为约2.5至约10mg/kg,更优选约2.5至约5mg/kg。还优选一种方法,其中所述神经肽-2受体激动剂的施用剂量为约5至约10mg/kg。
在如上所述的方法中,优选神经肽-2受体激动剂,其中X选自下列各项:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪。
在本发明还有的另一个实施方案中,提供神经肽-2受体激动剂,其具有PYY3-36衍生物,其氨基酸残基5-24被长度为约8至约11埃的部分所替代。
现在进一步通过下列详细描述和附图举例说明本发明,从中可以获取更多的实施方案、特征和优势。
本发明涉及PYY3-36的类似物,其中氨基酸残基5-24被诸如例如Pqa或Cms的部分所替代。例如,本发明提供式PYY3-4-Pqa-PYY25-36的化合物:
和式PYY3-4-Cms-PYY25-36的化合物:
本发明进一步提供下式化合物:
在上述结构中,按照常规命名法,基团-X-CH2-CH2-O-X-是指聚乙二醇部分的重复乙二醇单元,即基团-(CH2-CH2-O)n-。相应地选择″n″以获得所需聚乙二醇单元的所需分子量,优选约10′000(n约为227)或约30′000(n约为682)。使用天然PYY3-36的NMR-衍生结构作为指导,在本文中提供类似物,其具有替代PYY3-36的氨基酸残基5-24的部分。这些部分的实例包括N-哌嗪-1-基-4-(3H)-喹唑啉酮-3-乙酸(Pqa)和N-(5-O-羧甲基)-5-羟色铵(Cms)。该部分典型地是刚性的并有利地稳定分子的三级结构,由此产生具有所需功效和药代动力学和药理学性质的截短类似物。所述部分典型地长度为约8至约11埃,优选长度为约9至约11埃,更优选长度为约9至约10埃,还更优选长度为约8至约10,仍更优选长度为约8至约9埃。
应当理解,本发明不限于本文所述的本发明的具体实施方案,因为可以进行具体实施方案的改变并且仍落入后附权利要求的范围内。还应当理解,所用的术语是为了描述具体实施方案而不意欲是限制性的。实际上,本发明的范围将由后附权利要求所确定。
尽管类似于或等价于本文所述的那些的任何方法、装置和材料可以用于实施或检验本发明,然而现在描述优选的方法、装置和材料。
本发明的代表性化合物可以通过用于在氨基酸之间形成肽键的任何已知常规方法容易地合成。这些常规方法包括例如任何溶液相方法,该方法允许氨基酸或其残基(具有它的羧基和其它受保护的反应性基团)的游离α-氨基基团和另一个氨基酸或其残基(具有它的氨基或其它保护的反应性基团)的游离的伯羧基基团之间的缩合。
这些用于合成本发明新型化合物的常规方法包括例如任何固相肽合成法。在该方法中,新化合物的合成可以如下进行:按照固相法的一般原理,顺序将所需氨基酸残基每次一个结合到生长的肽链上。这些方法公开在例如Merrifield,R.B.,J.Amer.Chem.Soc.85,2149-2154(1963);Barany等,The Peptides,Analysis,Synthesis and Biology,Vol.2,Gross,E.和Meienhofer,J.,Eds.Academic Press 1-284(1980)中,其通过参考结合于此。
肽化学合成常见的是用适当的保护基将各种氨基酸部分的反应性侧链基团进行保护,这将防止在该位点的化学反应发生,直至保护基被最终去除。通常还常见的是在该实体在羧基上反应时,将氨基酸或其片段上的α氨基基团进行保护,接着选择性去除α氨基酸保护基,使得可以在该位点进行随后的反应。尽管关于固相合成法公开了特定的保护基,应当理解,在溶液相合成中每个氨基酸可以被常规用于各个氨基酸的保护基保护。
α氨基可以被选自下列各项的适当的保护基保护:芳族氨基甲酸乙酯类型的保护基,如烯丙氧羰基,苄氧羰基(Z)和取代的苄氧羰基,如对氯苄氧羰基,对硝基苄氧羰基,对溴苄氧羰基,对联苯基-异丙氧羰基,9-芴基甲氧羰基(Fmoc)和对甲氧基苄氧羰基(Moz);脂族氨基甲酸乙酯类型的保护基,如叔丁氧羰基(Boc),二异丙基甲氧羰基,异丙氧羰基,和烯丙氧羰基。这里,Fmoc最优选用于α氨基保护。
胍基可以通过选自下列各项的适当保护基保护:硝基,对甲苯磺酰基(Tos),(Z,)五甲基色烷磺酰基(Pmc),4-甲氧基-2,3,6,-三甲基苯磺酰基(Mtr),(Pmc),并且(Mtr)最优选用于精氨酸(Arg)。
ε-氨基基团可以通过选自下列各项的适当保护基保护:2-氯苄氧羰基(2-Cl-Z),2-溴苄氧羰基(2-Br-Z)-和t-丁氧羰基(Boc)。对于(Lys),Boc是最优选的。
羟基(OH)可以通过选自下列各项的适当的保护基进行保护:苄基(Bzl),2,6二氯苄基(2,6diCl-Bzl),和叔丁基(t-Bu),对于(Tyr),(Ser)和(Thr),(tBu)是最优选的。
β-和γ-酰胺基团可以通过选自下列各项的适当的保护基进行保护:4-甲基三苯甲基(Mtt),2,4,6-三甲氧基苄基(Tmob),4,4-二甲氧基dityl双-(4-甲氧基苯基)-甲基(Dod)和三苯甲基(Trt)。对于(Asn)和(Gln),Trt是最优选的。
吲哚基团可以通过选自下列各项的适当的保护基进行保护:甲酰基(For),基(Mesityl)-2-磺酰基(Mts)和叔丁氧羰基(Boc)。对于(Trp),Boc是最优选的。
咪唑基可以通过选自下列各项的适当的保护基进行保护:苄基(Bzl),-叔丁氧羰基(Boc),和三苯甲基(Trt)。对于(His),Trt是最优选的。
所有的溶剂,异丙醇(iPrOH),二氯甲烷(CH2Cl2),二甲基甲酰胺(DMF)和N-甲基吡咯啉酮(NMP)购自Fisher或Burdick & Jackson并且在不另外蒸馏下使用。三氟乙酸商购自Halocarbon或Fluka并且在不进一步纯化下使用。
二异丙基碳二亚胺(DIC)和二异丙基乙胺(DIPEA)购自Fluka或Aldrich并且在不进一步纯化下使用。羟基苯并三唑(HOBT)、二甲硫(DMS)和1,2-乙二硫酚(EDT)购自Sigma Chemical Co.并且在不进一步纯化下使用。保护的氨基酸通常是L构型并且商购自Bachem,或Neosystem。这些试剂的纯度在使用前通过薄层色谱法、NMR和熔点证实。二苯甲基胺树脂(BHA)是获自Bachem或Advanced Chemtech的苯乙烯-1%二乙烯基苯(100-200或200-400目)的共聚物。这些树脂的总氮含量通常为0.3-1.2meq/g。
在LDC装置上进行高效液相色谱法(HPLC),所述LDC装置由Constametric I和III泵,Gradient Master溶剂编程器和混合器,以及Spectromonitor III可变波长UV检测器组成。以反相模式使用Vydac C18柱(0.4×30cm)进行分析HPLC。在Vaydac柱(2×25cm)上进行制备HPLC分离。
在优选实施方案中,通过使用Merrifield,(J.Amer.Chem.Soc.,85,2149(1963))一般描述的方法,固相合成制备肽,但是如先前所述,可以使用本领域已知的其它等同的化学合成。固相合成从肽的C-末端开始,将保护的α-氨基酸偶联至适当的树脂。该原材料可以通过将α-氨基-保护的氨基酸通过酯键连接到对-苄氧基苄基醇(Wang)树脂上,或通过Fmoc-接头,如对((R,S)-α-(1-(9H-芴-9-基)-甲氧基甲酰胺基)-2,4-二甲氧基苄基)-苯氧基乙酸(Rink接头)之间的酰胺键连接到二苯甲基胺(BHA)树脂来制备。羟基甲基树脂的制备是本领域公知的。Fmoc-接头-BHA树脂支持体是可商购的并且通常当被合成的所需肽在C-末端具有未取代的酰胺时使用。
典型地,使用氨基酸或模拟物的Fmoc保护形式,用2-5当量的氨基酸和适当的偶联剂,将氨基酸或模拟物偶联到Fmoc-接头-BHA树脂上。在偶联后,可以洗涤树脂并在真空下干燥。氨基酸在树脂上的负载可以通过对等分试样的Fmoc-氨基酸树脂的氨基酸分析、或通过UV分析测定Fmoc基团来确定。任何未反应的氨基可以通过将树脂与在二氯甲烷中的乙酐和二异丙基乙胺反应来加帽。
将树脂进行几个重复循环以将氨基酸顺序加入。在碱性条件下去除α氨基Fmoc保护基。在DMF中的哌啶,哌嗪或吗啉(20-40%v/v)可以用于该目的。优选使用DMF中的40%哌啶。
在去除α氨基保护基之后,将随后保护的氨基酸以所需顺序逐步偶联以获得中间体,保护的肽-树脂。在肽的固相合成中用于氨基酸偶联的活化试剂是本领域公知的。例如,用于该合成的适当试剂是苯并三唑-1-基氧基-三-(二甲基氨基)鏻六氟磷酸盐(BOP),溴-三-吡咯烷子基-鏻六氟磷酸盐(PyBroP),2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HBTU),和二异丙基碳二亚胺(DIC)。这里优选HBTU和DIC。可以使用Barany和Merrifield描述的其它活化剂(在The Peptides,Vol.2,J.Meienhofer,ed.,Academic Press,1979,pp 1-284中)。可以将各种试剂如1羟基苯并三唑(HOBT),N-羟基琥珀酰亚胺(HOSu)和3,4-二氢-3-羟基-4-氧代-1,2,3-苯并三嗪(HOOBT)加入偶联混合物中,以便最优化合成循环。这里优选HOBT。
用于典型的合成循环的方案如下:
方案1
步骤 | 试剂 | 时间 |
1234567891011 | DMF20%哌啶/DMF20%哌啶/DMFDMFiPrOHDMF偶联DMFiPrOHDMFCH2Cl2 | 2×30秒1min15min2×30秒2×30秒3×30秒60min-18小时2×30秒1×30秒1×30秒2×30秒 |
将用于所有洗涤和偶联的溶剂量至10-20ml/g树脂的体积。贯穿合成的偶联反应通过Kaiser Ninhydrin试验监视,以确定完成的程度(Kaiser等Anal.Biochem.34,595-598(1970))。对于Fmoc-Arg(Pmc)和对于空间位阻的酸与仲胺的偶联观察到缓慢反应动力学。任何不完全的偶联反应或者与新鲜制备的活化氨基酸重新偶联,或者如上所述通过用乙酐处理肽树脂来加帽。将完全装配的肽-树脂在真空中干燥数小时。
对于每种化合物,去除封闭基团并从树脂上裂解肽。例如,每克树脂用100μL乙二硫酚,100μL二甲硫,300μL苯甲醚,和9.5mL三氟乙酸,在室温下处理肽树脂180min。或备选地,每克树脂用1.0mL三异丙基硅烷和9.5mL三氟乙酸,在室温下处理肽树脂180min。将树脂滤去,滤液在猝冷的乙醚中沉淀。将沉淀物离心并滗析乙醚层。
将残余物用两个或三个体积的Et2O洗涤并再离心。将粗产物在真空下干燥。
通过在反相Vydac C-18柱(50×250mm.300A,10-15μm)上的高效液相色谱法(HPLC)在Shimadzu LC-8A系统上进行粗制肽的纯化。将肽在最小体积的0.1 AcOH/H2O或CH3CH/H2O中注射到柱中。梯度洗脱通常以2%B缓冲液开始,70分钟内2%-70%B,(缓冲液A:0.1%TFA/H2O,缓冲液B:0.1%TFA/CH3CN),流速50ml/min。在220/280nm下进行UV检测。分离含有产物的级分并在Shimadzu LC-10AT分析系统上判断它们的纯度,其中使用反相Ace C18柱(4.6×50mm),流速为2ml/min.,10分钟内梯度(2-70%)(缓冲液A:0.1%TFA/H2O,缓冲液B:0.1%TFA/CH3CN))。将判断为高纯度的级分合并和冻干。
最终产品的纯度通过在如上所述的反相柱上的分析HPLC检查。所有产品的纯度据判断为大约95-99%。所有的终产品还进行快原子轰击质谱(FAB-MS)或电雾化质谱(ES-MS)。所有产品产生了预期的在可接受范围内的母体M+H离子。
Y2R激动剂导致人类肥胖症的小鼠模型中食物摄取的减少。因此,这些化合物的施用激动Y2受体活性,其对于减少食物摄取和调节体重是重要的。按照实施例78中的体内活性实验,对于所选的本发明的类似物(实施例5,44,73和74)证明了食物摄取的减少,结果总结在图7,8,9和10中。
本发明的化合物可以以药用盐的形式提供。优选的盐的实例是与药用有机酸以及聚合酸形成的那些和与无机酸形成的盐,所述有机酸如乙酸、乳酸、马来酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、水杨酸、甲磺酸、甲苯磺酸、三氟乙酸或双羟萘酸,所述聚合酸如鞣酸或羧甲基纤维素,所述无机酸如氢卤酸(例如,盐酸),硫酸,或磷酸等。可以使用本领域技术人员已知的任何获得药用盐的方法。
如上所述,已经发现本发明的新化合物是神经肽-2受体的激动剂。本发明的化合物因此可以用于治疗和/或预防受神经肽-2受体激动剂调节的疾病,特别是肥胖症。
本发明因此还涉及药物组合物,其包含如上定义的化合物和药用载体和/或佐剂。
本发明同样包括如上所述的化合物,其用作治疗活性物质,特别是作为用于治疗和/或预防受神经肽-2受体激动剂调节的疾病的治疗活性物质,特别是作为用于治疗和/或预防肥胖症的治疗活性物质。
在另一个优选实施方案中,本发明涉及用于预防和/或治疗受神经肽-2受体激动剂调节的疾病的方法,特别是用于预防和/或治疗肥胖症的方法,该方法包括向人或动物施用如上定义的化合物。
本发明还涉及如上定义的化合物用于治疗和/或预防受神经肽-2受体激动剂调节的疾病的应用,特别是用于治疗和/或预防肥胖症的应用。
本发明还涉及如上定义的化合物在制备用于治疗和/或预防受神经肽-2受体激动剂调节的疾病的药物中的应用,所述药物特别是用于治疗和/或预防肥胖症。这些药物包含如上所述的化合物。
在本发明方法的实施中,将有效量的任何本发明的肽或任何本发明的肽的组合或其药用盐的组合经由任何常规的和本领域可接受的方法、或者单独或者组合施用。化合物或组合物因此可以通过以下方式施用:口服(例如口腔),舌下,肠胃外(例如,肌内,静脉内,或皮下),直肠(例如,通过栓剂或洗剂),透皮(例如,皮肤电穿孔)或通过吸入(例如通过气溶胶),和以固体、液体或气体剂型的形式,包括片剂和混悬剂。给药可以以单一单位剂量形式连续治疗或随意以单一剂量治疗进行。治疗组合物还可以是油乳剂或与亲油性盐如双羟萘酸结合的分散体的形式,或者是用于皮下或肌内给药的生物可降解的缓释组合物的形式。
因此,当症状的减轻特别需要或可能危急时,实施本发明的方法。备选地,本发明的方法有效实施为连续或预防性治疗。
用于制备由此的组合物的有用药物载体可以是固体,液体或气体;因此,组合物可以采取片剂,丸剂,胶囊,栓剂,粉末,肠溶包衣或其它保护的制剂(例如结合在离子-交换树脂上或包装在脂蛋白泡囊中),缓释制剂,溶液,混悬剂,酏剂,气溶胶等形式。载体可以选自各种油类,包括石油、动物、植物或合成来源的那些,例如花生油,大豆油,矿物油,芝麻油等。水、盐水、葡萄糖溶液和二元醇是优选的液体载体,特别是(当与血液等渗时)用于注射液。例如,用于静脉内给药的制剂包括活性成分的无菌水溶液,其制备如下:将固体活性成分溶解在水中,产生水溶液,并使得溶液无菌。适当的药用赋形剂包括淀粉,纤维素,滑石,葡萄糖,乳糖,滑石,明胶,麦芽,大米,面粉,白垩,硅石,硬脂酸镁,硬脂酸钠,单硬脂酸甘油酯,氯化钠,脱脂奶粉,甘油,丙二醇,水,乙醇等。组合物可以加入常规药物添加剂,如防腐剂,稳定剂,润湿剂或乳化剂,用于调节渗透压的盐,缓冲剂等。适当的药用载体和它们的制剂在E.W.Martin的Remington′s Pharmaceutical Sciences中描述。这些组合物在任何情况下将含有有效量的活性化合物以及适当的载体,以便制备用于适当给药给接受者的适当剂型。
本发明的化合物的剂量取决于许多因素,如例如,给药方式,受试者的年龄和体重,和待治疗的受试者的病症,并且最终将由主治医生或兽医所决定。这样的由主治医生或兽医确定的活性化合物的量在本文中和在权利要求中称为“有效量”。例如,用于鼻内给药的剂量典型地在约1至约100mg/kg体重的范围内;并且用于皮下给药的剂量典型地在约0.001至约50mg/kg体重的范围内。
优选地,本发明的化合物的剂量为约2.5至约10mg/kg。最优选地,剂量是约2.5,约5和约10mg/kg。
现在将在以下列出的实施例中进一步描述本发明,其意欲仅仅作为举例说明而不限制本发明的范围。
实施例
实施例1
制备Fmoc-接头-BHA树脂
将二苯甲基胺共聚苯乙烯-1%二乙烯基苯交联树脂(10.0g,9.3mequiv,100-200ASTM目,Advanced ChemTech)溶胀在100mL CH2Cl2中,过滤并连续用100ml的各个CH2Cl2,6%DIPEA/CH2Cl2(两次),CH2Cl2(两次)洗涤。树脂用在100mL 25%DMF/CH2Cl2中的对-((R,S)-α-(1-(9H-芴-9-基)-甲氧基甲酰胺基)-2,4-二甲氧基苄基)-苯氧基乙酸(Fmoc-接头)(7.01g,13.0mmole)、N-羟基苯并三唑(2.16g,16.0mmole)和二异丙基-碳二亚胺(2.04ml,13.0mmol)在室温下处理24小时。将树脂过滤并连续用100ml各自CH2Cl2(两次),异丙醇(两次),DMF,和CH2Cl2(三次)洗涤。Kaiser Ninhydrin分析是阴性的。将树脂在真空下干燥,获得16.12g的Fmoc-接头-BHA树脂。将一部分该树脂(3.5mg)进行Fmoc脱保护和定量UV分析,其显示负载为0.56mmol/g。
实施例2
使用芴基甲氧羰基(Fmoc)化学,通过Applied Biosystem 433A合成仪合成肽的方案
对于通过Applied Biosystem 433A合成仪(Foster City,CA)的0.25mmol规模的肽合成,使用FastMoc 0.25mmole循环,使用树脂取样或非树脂取样,41mL反应容器。将Fmoc-氨基酸树脂与2.1g NMP,2g的在DMF中的0.45M HOBT/HBTU和2M DIEA溶解,然后转移到反应容器中。
用模块“BADEIFD,”表示基本的FastMoc偶联循环,其中每个字母表示一个模块。例如:
B表示用于Fmoc脱保护的模块,使用20%哌啶/NMP和相关洗涤,并且读取30min(或者UV监视或电导率);
A表示用0.45M HBTU/HOBt和2.0M DIEA激活柱体中氨基酸并用N2鼓泡混合的模块;
D表示在反应容器中树脂的NMP洗涤的模块;
E表示将活化氨基酸转移至用于偶联的反应容器的模块;
I表示反应容器的10分钟等待时期的模块,其中断断续续地涡旋;和
F表示用于清洗柱体、偶联约10分钟和排干反应容器的模块。
偶联典型地通过一次或多次增加模块“I”而延展。例如,通过执行程序“BADEIIADEIFD”进行双偶联。可以提供其它模块,例如用于二氯甲烷洗涤的c和用于用乙酐加帽的“C”。单独的模块也是可更改的,例如通过改变各种功能的定时,如转移时间,以便改变被转移的溶剂或试剂的量。
以上的循环典型地用于偶联一个氨基酸。然而对于合成四肽,重复循环并且连贯起来。例如,将BADEIIADEIFD用于偶联第一个氨基酸,接着BADEIIADEIFD偶联第二个氨基酸,接着BADEIIADEIFD偶联第三个氨基酸,接着BADEIIADEIFD偶联第四个氨基酸,接着BIDDcc用于最终脱保护和洗涤。
实施例3
制备
H-Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(PYY1-36)(SEQ ID NO:3)
使用Fmoc化学,在Applied Biosystem 433A合成仪上合成上述肽。使用实施例2所述的模块,对于双偶联对合成仪进行编程。合成在0.25mmol规模上进行,使用来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)。在合成结束时,将树脂转移到振荡器上的反应容器中用以裂解。在室温下使用13.5mL 97%TFA/3%H2O和1.5mL三异丙基硅烷180分钟,将肽从树脂上裂解。将脱保护溶液加入100mL冷ET2O中,用1mL TFA和30mL冷ET2O洗涤以沉淀肽。将肽在2×50mL聚丙烯管中离心。将来自单个管的沉淀合并在单一管中,并用冷ET2O洗涤3次,并在干燥器中在室内真空(house vacuum)下干燥。
将粗制物质通过在Pursuit C18-Column(250×50mm,10μm粒度)上的制备HPLC纯化,并用90分钟内2-70%B(缓冲液A:0.1%TFA/H2O;缓冲液B:0.1%TFA/CH3CN)的线性梯度洗脱,流速60mL/min,并且220/280nm检测。收集级分并通过分析HPLC检查。将含有纯产物的级分合并和冻干而获得65mg(6%)的白色无定形粉末。(ES)+-LCMS m/e计算值(“calcd”)C194H295N55O57 4309.85,实测值4309.15。
实施例4
制备
H-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(PYY3-36)(SEQ ID NO:4)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成并按照实施例3中的方法纯化,获得151mg(15%)白色无定形粉末。(ES)+-LCMS m/e计算值C180H279N53O54 4049.55实测值4050.40.
实施例5
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成并按照实施例3中的方法纯化,获得148mg(9%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H155N33O21 2131.53实测值2130.56.
实施例6
制备
Ac-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将酰化(actylation)周期增加到ABI-方案中)并按照实施例3中的方法纯化,获得150mg(27%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H157N33O22 2171.57实测值2171.4.
实施例7
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Ala-Arg-Tyr-NH2(SEQ ID NO:6)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的34位)并按照实施例3中的方法纯化,获得142mg(27%)白色无定形粉末。(ES)+-LCMS m/e计算值C96H150N32O20 2072.47实测值2072.4
实施例8
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Ala-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:7)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的32位)并按照实施例3中的方法纯化,获得167mg(32%)白色无定形粉末。(ES)+-LCMS m/e计算值C97H151N33O20 2099.49实测值2100.3
实施例9
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Ala-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:8)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的31位)并按照实施例3中的方法纯化,获得105mg(20%)白色无定形粉末。(ES)+-LCMS m/e计算值C96H149N33O212101.47实测值2102.1
实施例10
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Ala-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:9)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的30位)并按照实施例3中的方法纯化,获得167mg(27%)白色无定形粉末。(ES)+-LCMS m/e计算值C95H147N33O212087.44实测值2087.7
实施例11
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Ala-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:10)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的29位)并按照实施例3中的方法纯化,获得142mg(27%)白色无定形粉末。(ES)+-LCMS m/e计算值C97H152N32O202086.50实测值2086.50.
实施例12
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Ala-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:11)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的28位)并按照实施例3中的方法纯化,获得164mg(31%)白色无定形粉末。(ES)+-LCMS m/e计算值C95H147N33O21 2087.44实测值2087.40.
实施例13
制备
H-Ile-Lys-Pqa-Arg-His-Ala-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:12)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的27位)并按照实施例3中的方法纯化,获得132mg(26%)白色无定形粉末。(ES)+-LCMS m/e计算值C92H149N33O202037.42实测值2037.60.
实施例14
制备
H-Ile-Lys-Pqa-Arg-Ala-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:13)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的26位)并按照实施例3中的方法纯化,获得76mg(15%)白色无定形粉末。(ES)+-LCMS m/e计算值C95H151N31O21 2063.46实测值2064.0
实施例15
制备
H-Ile-Lys-Pqa-Ala-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:14)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的25位)并按照实施例3中的方法纯化,获得152mg(30%)白色无定形粉末。(ES)+-LCMS m/e计算值C95H146N30O212043.13实测值2043.4.
实施例16
制备
H-Ile-Ala-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的4位)并按照实施例3中的方法纯化,获得72mg(14%)白色无定形粉末。(ES)+-LCMS m/e计算值C95H146N32O212072.44实测值2071.2
实施例17
制备
Ac-Ile-Ala-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例16的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成,其中将酰化循环加入方案,并按照实施例3中的方法纯化,获得234mg(44%)白色无定形粉末。(ES)+-LCMS m/e计算值C97H148N32O222114.46实测值2114.7.
实施例18
制备
H-Ala-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala插入序列的3位)并按照实施例3中的方法纯化,获得196mg(38%)白色无定形粉末。(ES)+-LCMS m/e计算值C95H147N33O21 2087.45实测值2086.5.
实施例19
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-(D)Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Tyr插入序列的36位)并按照实施例3中的方法纯化,获得114mg(21%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O212129.52实测值2129.10.
实施例20
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-(D)Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Arg插入序列的35位)并按照实施例3中的方法纯化,获得221mg(42%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O212129.52实测值2129.10.
实施例21
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-(D)Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Arg插入序列的33位),并按照实施例3中的方法纯化,获得174mg(32%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O212129.52实测值2128.4.
实施例22
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-(D)Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Val插入序列的31位)并按照实施例3中的方法纯化,获得67mg(12%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.52实测值2129.10.
实施例23
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-(D)Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Leu插入序列的30位)并按照实施例3中的方法纯化,获得190mg(36%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O212129.52实测值2129.10.
实施例24
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-(D)Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Asn插入序列的29位)并按照实施例3中的方法纯化,获得50mg(10%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2128.80.
实施例25
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-(D)Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Leu插入序列的28位)并按照实施例3中的方法纯化,获得188mg(35%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2129.40.
实施例26
制备
H-Ile-Lys-Pqa-Arg-His-(D)Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Tyr插入序列的27位)并按照实施例3中的方法纯化,获得119mg(22%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2129.70.
实施例27
制备
H-Ile-Lys-Pqa-Arg-(D)His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)His插入序列的26位)并按照实施例3中的方法纯化,获得84mg(16%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2128.80.
实施例28
制备
H-Ile-Lys-Pqa-(D)Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Arg插入序列的25位)并按照实施例3中的方法纯化,获得85mg(16%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2128.80.
实施例29
制备
H-Ile-(D)Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Lys插入序列的4位)并按照实施例3中的方法纯化,获得165mg(31%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2129.10.
实施例30
制备
H-(D)Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Ile插入序列的3位)并按照实施例3中的方法纯化,获得84mg(8%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N33O21 2129.53实测值2129.40.
实施例31
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-(NMe)Tyr-NH2(SEQ ID NO:15)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Tyr插入序列的36位)并按照实施例3中的方法纯化,获得90mg(17%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H157N33O212143.56实测值2143.50.
实施例32
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH2(SEQ ID NO:16)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Arg插入序列的35位)并按照实施例3中的方法纯化,获得32mg(6%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.50.
实施例33
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-(NMe)Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:17)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Arg插入序列的33位)并按照实施例3中的方法纯化,获得40mg(7%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.20.
实施例34
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-(NMe)Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:18)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Thr插入序列的32位)并按照实施例3中的方法纯化,获得115mg(21%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.20.
实施例35
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-(NMe)Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:19)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Val插入序列的31位)并按照实施例3中的方法纯化,获得60mg(11%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.20.
实施例36
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-Leu-Asn-(NMe)Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:20)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基leu插入序列的30位)并按照实施例3中的方法纯化,获得91mg(17%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2142.90.
实施例37
制备
H-Ile-Lys-Pqa-Arg-His-Tyr-(NMe)Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:21)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基leu插入序列的28位)并按照实施例3中的方法纯化,获得153mg(28%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2142.90.
实施例38
制备
H-Ile-Lys-Pqa-Arg-His-(NMe)Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:22)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Tyr插入序列的27位)并按照实施例3中的方法纯化,获得76mg(14%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2142.90.
实施例39
制备
H-Ile-Lys-Pqa-Arg-(NMe)His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:23)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基His插入序列的26位)并按照实施例3中的方法纯化,获得93mg(7%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.53实测值2143.50.
实施例40
制备
H-Ile-Lys-Pqa-(NMe)Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:24)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Arg插入序列的25位)并按照实施例3中的方法纯化,获得33mg(6%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.50.
实施例41
制备
H-Ile-NMeLys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Lys插入序列的4位)并按照实施例3中的方法纯化,获得156mg(29%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.20.
实施例42
制备
H-NMeIle-Lys-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Ile插入序列的3位)并按照实施例3中的方法纯化,获得203mg(38%)白色无定形粉末。(ES)+-LCMS m/e计算值C99H155N33O212143.56实测值2143.20.
实施例43
制备
H-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Nle插入序列的4位)并按照实施例3中的方法纯化,获得60mg(11%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H153N32O21 2114.52实测值2113.80.
实施例44
制备
Ac-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将酰化循环加入方案)并按照实施例3中的方法纯化,获得41mg(8%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H154N32O22 2156.56实测值2156.10.
实施例45
制备
Ac-Ile-Nle-Pqa-Phe-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:25)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Phe插入序列的25位)并按照实施例3中的方法纯化,获得92mg(7%)白色无定形粉末。(ES)+-LCMS m/e计算值C103H151N29O22 2147.53实测值2148.00.
实施例46
制备
H-Ile-Lys-Pqa-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:26)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Trp插入序列的27位)并按照实施例3中的方法纯化,获得30mg(6%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H154N34O20 2153.56实测值2152.20
实施例47
制备
H-Ile-Lys-Pqa-Ala-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:27)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ala 25和Trp 27插入序列)并按照实施例3中的方法纯化,获得50mg(9%)白色无定形粉末。(ES)+-LCMS m/e计算值C97H147N31O20 2067.46实测值2067.30.
实施例48
制备
Ac-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-(D)Tyr-NH2
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(D)Tyr插入序列的36位)并按照实施例3中的方法纯化,获得104mg(19%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H154N32O22 2156.54实测值2157.00.
实施例49
制备
Ac-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-N-甲基Tyr-NH2(SEQ ID NO:15)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将N-甲基Tyr插入序列的36位)并按照实施例3中的方法纯化,获得28mg(5%)白色无定形粉末。(ES)+-LCMS m/e计算值C101H156N32O222170.57实测值2170.50.
实施例50
制备环Lys28-Asp32
Ac-Ile-Nle-Pqa-Arg-His-Tyr-Lys-Asn-Leu-Val-Asp-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:28)
通过在ABI 433合成仪上使用标准方案的自动合成和0.25mM规模的手工合成的组合制备该肽。使用ABI方案合成片段Fmoc-Asn(Trt)-Leu-Val-Asp(2Pip)-Arg(Pmc)-Gln(Trt)-Arg(Pmc)-Tyr(OBut)-BHA树脂(SEQ ID NO:29)并然后手工延长获得Fmoc-Ile-Nle-Pqa-Arg(Pmc)-His(Trt)-Tyr(OBut)-Lys-Asn(Trt)-Leu-Val-Asp-Arg(Pmc)-Gln(Trt)-rg(Pmc)-Tyr(OBut)-BHA树脂(SEQ ID NO:30)。在完成自动合成后,将肽树脂转移至手工固相容器并用二氯甲烷和DMF洗涤多次。将Fmoc-Lys(Mtt)1.2g(2.0mM 8eqv)作为固体加入并加入15mL DMF,接着1.2mL Dic(7mM 28eqv.)。使得偶联进行直至获得阴性或接近阴性茚三酮。如果没有获得阴性茚三酮,将树脂用Ac2O 6mL,DIEA 1mL和DMF 18mL酰化30分钟,用茚三酮校验完成。树脂然后用3 X DMF和4 X CH2Cl2洗涤。使用CH2Cl2中的2%TFA将Lys(Mtt)和Asp(2Pip)脱保护10次。在脱保护后,将肽树脂用2 X CH2Cl2;2 X 6%TFA/CH2Cl2;2 X 6%DIEA/DMF和2 X DMF洗涤。侧链用HATU(240mg 0.625mM(2.5eqv.)和DIEA(175μL 1.0mM(4eqv))环化,用茚三酮监视直至阴性。
在完成环化后,将肽树脂转移至ABI容器用于延伸至Fmoc-Arg(Pmc)-His(Trt)-Tyr(OBut)-Lys-Asn(Trt)-Leu-Val-Asp-Arg(Pmc)-Gln(Trt)-Arg(Pmc)-Tyr(OBut)-BHA树脂(SEQ ID NO:30)。将Fmoc-Pga-OH(160mg,313mM(1.25eqv))和HOBt(5mg,313mM(1.25eqv))作为固体加入并加入15mL DMF,接着加入1.2mL Dic(7mM 28eqv.)。使得偶联在室温下过夜进行(通常18hr.)。在用DMF洗涤4次后,用茚三酮监视偶联并通常是阴性的。在标准脱保护和洗涤后,将Fmon-Nle-OH(1.2g,3.0mM(12eqv))用6.6mL的在DMF中的0.45M HBTT/HOBt预活化3分钟,并加入肽树脂。使得偶联进行3至4小时,排干反应容器,用DMF洗涤4次。用chlorinal(在DMAc中的2%乙醛和2%四氯-1,4-苯醌)监视该偶联。如果该偶联被判断为不完全,将树脂重新偶联过夜。当偶联完成时,将树脂脱保护并洗涤,用6.6mL的DMF中的0.45M HBTT/HOBt将Fmoc-Ile(1.2g,3.0mM(12eqv))预活化3分钟,并加入肽树脂。使得偶联进行3至4小时,将反应容器排干并用DMF洗涤4次。用茚三酮监视该偶联并且通常是阴性的。将树脂脱保护和洗涤,用Ac2O 6mL,DIEA 1mL和DMF 18mL酰化30分钟,用茚三酮校验完成,直至获得阴性或接近阴性茚三酮。如果没有获得阴性茚三酮,将树脂用Ac2O 6mL,DIEA 1mL和DMF 18mL酰化30分钟,用茚三酮校验完成。
在合成完成后,将树脂用CH2Cl2洗涤4次,并在N2气流下干燥。将肽脱保护并用1.5mL三异丙基硅烷和13.5mL 97%TFA/3%H2O从树脂上裂解180分钟。将脱保护溶液加入100mL冷ET2O,用1mL TFA和30mL冷ET2O洗涤以沉淀肽,然后离心和在干燥器中在室内真空下干燥。
纯化粗制肽并通过实施例3所述的步骤冻干,获得49mg(9%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H151N33O22 2167.53实测值2167.80.
实施例51
制备
H-Ile-Lys-Cms-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成并按照实施例3中的方法纯化,获得44mg(8%)白色无定形粉末。(ES)+-LCMS m/e计算值C96H151N31O21 2075.47实测值2074.80.
实施例52
制备
H-Ile-Lys-Gly-Cms-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成并按照实施例3中的方法纯化,获得129mg(24%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H154N32O22 2132.52实测值2133.00.
实施例53
制备环Lys28-Aspu32
Ac-Ile-Nle-Cms-Arg-His-Tyr-Lys-Asn-Leu-Val-Asp-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:28)
按照实施例50公开的方法,通过在ABI 433上的自动合成和0.25mM规模的手工合成的组合制备该肽。将Fmoc-Cms-OH(151mg,313mM(1.25eqv))和HOBt(45mg,313mM(1.25eqv))作为固体加入,加入15mL DMF,接着加入1.2mL Dic(7mM 28eqv.)。使得偶联在室温下进行过夜(通常18小时)。
将粗制肽纯化和冻干,获得19mg(9%)白色无定形粉末。(ES)+-LCMSm/e计算值C98H149N31O22 2113.47实测值2113.80.
实施例54
制备
Ac-Ile-Nle-Pqa-Arg-His-Tic-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:31)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Tic插入序列的27位)并按照实施例3中的方法纯化,获得87mg(16%)白色无定形粉末。(ES)+-LCMS m/e计算值C101H154N32O21 2152.56实测值2152.50.
实施例55
制备
Ac-Ile-Nle-Pqa-Arg-His-Bip-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:32)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Bip插入序列的27位)并按照实施例3中的方法纯化,获得90mg(16%)白色无定形粉末。(ES)+-LCMS m/e计算值C106H158N32O21 2216.64实测值2217.00.
实施例56
制备
Ac-Ile-Nle-Pqa-Arg-His-Dip-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:33)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Dip插入序列的27位)并按照实施例3中的方法纯化,获得84mg(15%)白色无定形粉末。(ES)+-LCMS m/e计算值C106H158N32O21 2216.64实测值2217.30.
实施例57
制备
Ac-Ile-Nle-Pqa-Arg-His-(1)Nal-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:34)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(1)Nal插入序列的27位)并按照实施例3中的方法纯化,获得88mg(16%)白色无定形粉末。(ES)+-LCMS m/e计算值C104H156N32O21 2190.60实测值2190.61.
实施例58
制备
Ac-Ile-Nle-Pqa-Arg-His-(2)Nal-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:35)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(2)Nal插入序列的27位)并按照实施例3中的方法纯化,获得40mg(7%)白色无定形粉末。(ES)+-LCMS m/e计算值C104H156N32O21 2190.60实测值2191.20.
实施例59
制备
Ac-Ile-Nle-Pqa-Arg-His-(3,4,5trifluorPhe)-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:36)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将3,4,5,三氟Phe插入序列的27位)并按照实施例3中的方法纯化,获得101.4mg(18%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H151F3N32O21 2194.52实测值2194.20.
实施例60
制备
Ac-Ile-Nle-Pqa-Arg-His-
(2,3,4, 5,6-五氟Phe)-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:37)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将2,3,4,5,6,五氟Phe插入序列的27位)并按照实施例3中的方法纯化,获得122.5mg(22%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H149F5N32O212230.50实测值2230.50.
实施例61
制备
Ac-Ile-Nle-Pqa-Arg-(4-MeOApc)-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:38)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(4-MeO-Apc)插入序列的26位)并按照实施例3中的方法纯化,获得43mg(8%)白色无定形粉末。(ES)+-LCMS m/e计算值C108H164N30O232250.70实测值2250.60.
实施例62
制备
Ac-Ile-Nle-Pqa-Arg-(3-Pal)-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:39)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(3-Pal)插入序列的26位)并按照实施例3中的方法纯化,获得112mg(21%)白色无定形粉末。(ES)+-LCMS m/e计算值C102H155N31O22 2167.57实测值2167.20.
实施例63
制备
Ac-Ile-Nle-Pqa-Arg-(4-Pal)-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:40)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(4-Pal)插入序列的26位)并按照实施例3中的方法纯化,获得146mg(27%)白色无定形粉末。(ES)+-LCMS m/e计算值C102H155N31O22 2167.57实测值2167.20.
实施例64
制备Ac-Ile-Nle-Pqa-(3,4,5三氟Phe)-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:41)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(3,4,5三氟Phe)插入序列的25位)并按照实施例3中的方法纯化,获得55mg(10%)白色无定形粉末。(ES)+-LCMS m/e计算值C103H148F3N29O22 2201.50实测值2201.40.
实施例65
制备Ac-Ile-Nle-Pqa-(2,3,4,5,6五氟Phe)-His Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:42)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(2,3,4,5,6五氟Phe)插入序列的25位)并按照实施例3中的方法纯化,获得65mg(12%)白色无定形粉末。(ES)+-LCMS m/e计算值C103H146F5N29O22 2237.49实测值2237.70.
实施例66
制备
Ac-Aib-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(Aib)插入序列的3位)并按照实施例3中的方法纯化,获得32mg(6%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H150N32O22 2128.49实测值2128.00.
实施例67
制备
Ac-1,1-Aic-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(1,1Aic)插入序列的3位)并按照实施例3中的方法纯化,获得分离为PkA的外消旋混合物:31mg(6%)白色无定形粉末。(ES)+-LCMS m/e计算值C104H152N32O22 2202.57实测值2202.60.
实施例68
制备
Ac-1,1-Aic-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(1,1Aic)插入序列的3位)并按照实施例3中的方法纯化,获得分离为Pk.B的外消旋混合物:46mg(8%)白色无定形粉末。(ES)+-LCMS m/e计算值Pk B.C104H152N32O22 2202.57实测值2202.60.
实施例69
制备
Ac-2,2-Aic-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将(2,2Aic)插入序列的3位)并按照实施例3中的方法纯化,获得103mg(19%)白色无定形粉末。(ES)+-LCMS m/e计算值C104H152N32O22 2202.57实测值2202.30.
实施例70
制备
Ac-Ach-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Ach插入序列的3位)并按照实施例3中的方法纯化,获得81mg(15%)白色无定形粉末。(ES)+-LCMS m/e计算值C101H154N32O22 2168.55实测值2168.10.
实施例71
制备
Ac-Acp-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成(将Acp插入序列的3位)并按照实施例3中的方法纯化,获得95mg(18%)白色无定形粉末。(ES)+-LCMS m/e计算值C100H152N32O22 2154.53实测值2154.30.
实施例72
制备
H-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
将来自实施例1的Fmoc-接头-BHA树脂(450mg,0.25mmol)进行固相合成并按照实施例3中的方法纯化,获得80mg(15%)白色无定形粉末。(ES)+-LCMS m/e计算值C98H152N32O21 2114.51实测值2113.80.
实施例73
制备
PEG(10,000)-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
在以上结构中,基团-X-CH2-CH2-O-X-,按照通常命名法,是指聚乙二醇部分的重复乙二醇单元,即基团-(CH2-CH2-O)n-。相应地选择″n″以获得所需聚乙二醇单元的所需分子量。称出来自实施例72的15mg肽并溶解在50mM硼酸盐,pH7.4缓冲液中。称量107mg 10kDaPEG-SPA-NHS(Nektar)以获得2∶1 PEG∶肽摩尔比并加入溶解的肽。将反应混合物在室温下搅拌2小时,之后在20mM NaOAc,pH4.5缓冲液中稀释10倍,通过在S-Sepharose(Amersham)上的阳离子交换色谱法纯化。图1是10kDa PEG-PYY肽的HPLC色谱图。反应产生67.8%的10kDa肽。
将单-PEG化的PYY肽使用梯级NaCl梯度洗脱。典型地,所需的单-PEG化的肽用125mM NaCl洗脱。洗脱的PEG-PYY-样肽在Amicon超滤室中使用10kDa MW截止值的膜进行浓缩。然后用PBS渗滤10倍一次。
将实施例73的浓缩肽提交分析,测定和贮存在-20℃。图2是纯化的10kDa PEG-PYY肽的HPLC色谱图。10kDa肽的纯度被测定为97.6%。图3是图表,表示进行10kDa PEG-PYY肽的MALDI-TOF以证实分子量。
实施例74
制备
PEG(30,000)-Ile-Nle-Pqa-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ ID NO:5)
在以上结构中,基团-X-CH2-CH2-O-X-,按照通常命名法,是指聚乙二醇部分的重复乙二醇单元,即基团-(CH2-CH2-O)n-。相应地选择″n″以获得所需聚乙二醇单元的所需分子量。称出来自实施例72的15mg肽并溶解在50mM硼酸盐,pH7.4缓冲液中。称量244mg 30kDa PEG-SPA-NHS以获得2∶1 PEG∶肽摩尔比并加入到溶解的肽。将反应混合物在室温下搅拌2小时(图4),之后在20mM NaOAc,pH4.5缓冲液中稀释10倍,通过在S-Sepharose(Amersham)上的阳离子交换色谱法纯化。图4是30kDaPEG-PYY肽的HPLC色谱图。反应产生88.3%的30kDa肽。
将单-PEG化的PYY肽使用梯级NaCl梯度洗脱。典型地,所需的单-PEG化的肽用125mM NaCl洗脱。洗脱的PEG-PYY-样肽在Amicon超滤室中使用10kDa MW截止值的膜进行浓缩。然后用PBS渗滤10倍一次。将浓缩肽提交分析,测定和贮存在-20℃。图5是纯化的30kDa PEG-PYY肽的HPLC色谱图。30kDa肽的纯度被测定为98.4%。图6表示30kDaPEG-PYY肽的MALDI-TOF,其是进行用于证实分子量。
实施例75
来自实施例49的化合物的血浆稳定性
测量来自实施例49的肽的在人和小鼠血浆中的稳定性。在该实施例中,将140微克的来自实施例49的肽与300微升的人或小鼠血浆在37.5℃下温育0,40,90和150分钟。POSR温育每个样品在水中的0.1%乙酸中稀释50次。稀释样品然后通过LC/UV/MS分析并发现是稳定的。
实施例76
来自实施例32的化合物的血浆稳定性
测量来自实施例32的肽的在人和小鼠血浆中的稳定性。在该实施例中,将51微克的来自实施例32的肽与300微升的人或小鼠血浆在37.5℃下温育0,40,90和150分钟。POSR温育每个样品在水中的0.1%乙酸中稀释50次。稀释样品然后通过LC/UV/MS分析并发现是稳定的。
实施例77
cAMP激动剂测定
在本实施例中,使用下列材料:384-孔平板;Tropix cAMP-Screen试剂盒;cAMP ELISA系统(Applied Biosystems,cat.#T 1505;CS 20000);Forskolin(Calbiochem cat.#344270);细胞:HEK293/hNPY2R;生长培养基:Dulbecco’s modified eagle medium(D-MEM,Gibco);10%胎牛血清(FBS,Gibco),热-灭活;1%青霉素/链霉素(Pen 10000unit/ml:Strep 10000mg/ml,Gibco);500mg/ml G418(遗传霉素,Gibco cat.#11811-031);和接种培养基:DMEM/F12 w/o酚红(Gibco);10%FBS(Gibco,cat.#10082-147),热-灭活;1%青霉素/链霉素(Gibco,cat.#15140-122);500mg/ml G418(遗传霉素,Gibco,cat.#11811-031)。
在第一天,丢弃培养基,将单层细胞用10ml PBS/摇瓶(T225)洗涤。在用PBS滗析后,使用5ml VERSENE(Gibco,cat#1504006)以移动细胞(5min@37C)。将摇瓶轻微敲打并合并细胞悬浮液。每个摇瓶用10ml接种培养基漂洗,并在1000rpm下离心5分钟。将悬浮液合并和计数。
对于HEK293/hNPY2R,将悬浮液重悬浮在接种培养基中,密度为2.0X 105细胞/ml。使用Multi-drop分配器将50微升细胞(HEK293/hNPY2R-10,000细胞/孔)转移到384-孔平板中。将平板在37℃温育过夜。
第二天,检查细胞的75-85%汇合。使得培养基和试剂达到室温。在制备稀释液之前,使得在二甲亚砜(DMSO,Sigma,cat#D2650)中的刺激化合物的贮液升温至32℃,5-10min。在DMEM/F12中用0.5mM 3-异丁基-1-甲基黄嘌呤(IBMX,Calbiochem,cat#410957)和0.5mg/ml BSA制备稀释液。刺激培养基中的最终DMSO浓度是1.1%,Forskolin浓度为5μM。
在纸巾上用细胞平板的轻微倒转使细胞培养基流出。每孔放置50μL刺激培养基(每个浓度四个平行测定)。将平板在室温下温育30分钟,在显微镜下检查细胞的毒性。
在处理30分钟后,丢弃刺激培养基,加入50μl/孔测定裂解缓冲液(在Tropix试剂盒中提供)。将平板在37℃下温育45分钟。
将20μL裂解物从刺激平板转移到来自Tropix试剂盒的预包被的抗体平板(384-孔)中。加入10μL的AP缀合物和20μL抗-cAMP抗体。将平板在室温下在振荡同时温育1小时。然后将平板用洗涤缓冲液洗涤5次,每次洗涤每孔70μL。将平板抽干。加入30μL/孔的CSPD/Saphire-II RTU底物/增强物溶液,并在RT(振荡)温育45分钟。测量在光度计(VICTOR-V)中1秒/孔的信号。
实施例78
食物摄取体内减少测定
在本实施例中,将实施例5,44,73和74的化合物在四个分开实验中施用于四组小鼠,以测量对食物摄取的影响。将C57BL/6J雄性小鼠或DIO(饮食诱导的肥胖)雄性小鼠用于实验中,每个实验组8只小鼠。将小鼠保持在规则的光周期(6AM-开;6PM-关)。在无限制的获得水之前,将小鼠禁食24小时。在测试中,每只小鼠住一个笼子。
将实施例5和44的化合物腹膜内施用;将实施例73和74的化合物皮下施用。在剂量给药后1,2,4,6,和24小时测量食物摄取,结果表示在图7至10中。对于实施例73和74的化合物测量长时间间隔的食物摄取,并显示在图9和10中。在每个图中,在单个小鼠中测量累积和时间间隔食物消耗。对于每个时间间隔计算平均食物消耗和从载体的百分比变化。通过使用双-尾Student t-检验分析数据。图7至10显示,与对照相比,本发明的化合物在减少食物摄取方面有效。
实施例79
CaFlux测定
将Hek-293细胞用G蛋白嵌合体Gaqi9稳定转染,将潮霉素-B抗性基因进一步用人NPY2受体和G418抗生素选择转染。在潮霉素-B和G418两者中选择以后,测定单个克隆它们对PYY的反应。将转染的细胞在补充有10%胎牛血清、50μg/ml潮霉素-B、2mM谷氨酰胺、100U/ml青霉素、100μg/ml链霉素和250μg/ml G418的DMEM培养基中培养。将细胞用胰蛋白酶-EDTA收获并使用ViaCount试剂计数。将细胞悬浮体积用完全生长培养基调节至4.8×105细胞/ml。将25μL等分试样分配到384孔Poly-D赖氨酸包被的黑色/透明微量培养板(Falcon)中,将微量培养板在37℃ CO2培养箱中放置过夜。
通过将一小管的内容物(Express Kit)溶解在含有20mM HEPES和5mM的丙磺舒的1000ml Hank’s平衡盐溶液中来制备加样缓冲液(Calcium-3测定试剂盒,Molecular Devices)。将25μL稀释染料的等分试样分配到细胞平板中,然后将平板在37℃下温育1小时。
在温育期间,在HBSS(20mM HEPES)/0.05%BSA/1%DMSO中以3.5X所需浓度制备测试化合物,并转移到384孔平板中在FLIPR上使用。
在温育后,将细胞和化合物平板两者放至FLIPR并通过FLIPR将20μL稀释的化合物转移到细胞培养板。在测定中,每1.5秒从细胞培养板的全部384个孔自动获取荧光读数。获得5个读数以建立稳定的基线,然后将20μL样品迅速(30μL/秒)和同时加入细胞培养板的每个孔。在样品加入之前、期间和之后连续监视荧光总共100秒的消逝时间。测定在加入后每个孔中的响应(峰荧光的提高)。将在配体刺激之前来自每孔的最初荧光读数用作来自那个孔的数据的零基线值。响应表示为阳性对照的最大响应%。
本发明的化合物显示选择性的体外神经肽-2受体活性,如在cAMP测定(实施例77)和CaFlux测定(FLIPR)(实施例78)中显示。对于实施例3至74的体外结果、IC50和EC50的总结在以下表1中说明:
表1
实施例 | 序列 | Y2REC50(nM) | Y2RIC50(nM) | Y1REC50(nM) | Y4REC50(nM) |
FLIPR | cAMP | FLIPR | FLIPR | ||
3 | YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY(1-36) | 0.76 | 0.042 | 62 | 123 |
4 | IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY(3-36) | 2.93 | 0.032 | 557 | >5000 |
5 | IK-Pqa-RHYLNLVTRQRY | 3.2 | 0.032 | 373 | >5000 |
6 | Ac-IK-Pqa-RHYLNLVTRQRY | 0.58 | 0.026 | 184 | >5000 |
7 | IK-Pqa-RHYLNLVTRARY | 176 | 29 | >5000 | >5000 |
8 | IK-Pqa-RHYLNLVARQRY | 18.6 | 5.27 | >5000 | >5000 |
9 | IK-Pqa-RHYLNLATRQRY | 9.65 | 0.21 | >5000 | >5000 |
10 | IK-Pqa-RHYLNAVTRQRY | 4.85 | 0.25 | >5000 | >5000 |
11 | IK-Pqa-RHYLALVTRQRY | 38.3 | 3.11 | >5000 | >5000 |
12 | IK-Pqa-RHYANLVTRQRY | 6.25 | 0.24 | >5000 | >5000 |
13 | IK-Pqa-RHALNLVTRQRY | 10.8 | 1.39 | >5000 | >5000 |
14 | IK-Pqa-RAYLNLVTRQRY | 12.2 | 0.062 | >5000 | >5000 |
15 | IK-Pqa-AHYLNLVTRQRY | 25 | 0.639 | 3400 | >5000 |
16 | IA-Pqa-RHYLNLVTRQRY | 1.68 | 0.079 | 1000 | >5000 |
17 | Ac-IA-Pqa-RHYLNLVTRQRY | 2.47 | 0.247 | >5000 | 3017 |
18 | AK-Pqa-RHYLNLVTRQRY | 0.62 | 0.172 | >5000 | >5000 |
19 | IK-Pqa-RHYLNLVTRQR(D)Y | 3.5 | 1.09 | 3300 | >5000 |
20 | IK-Pqa-RHYLNLVTRQ(D)RY | 110 | 25 | >5000 | >5000 |
21 | IK-Pqa-RHYLNLVT(D)RQRY | 324 | 65 | >5000 | >5000 |
22 | IK-Pqa-RHYLNL(D)VTRQRY | 322 | 21 | >5000 | >5000 |
23 | IK-Pqa-RHYLN(D)LVTRQRY | 66 | 22 | >5000 | >5000 |
24 | IK-Pqa-RHYL(D)NLVTRQRY | 48 | 0.92 | 3800 | >5000 |
25 | IK-Pqa-RHY(D)LNLVTRQRY | 5.26 | 0.37 | 3800 | >5000 |
26 | IK-Pqa-RH(D)YLNLVTRQRY | 2.98 | 0.26 | 654 | >5000 |
27 | IK-Pqa-R(D)HYLNLVTRQRY | 12.3 | 3.18 | 431 | >5000 |
28 | IK-Pqa-(D)RHYLNLVTRQRY | 5.2 | 0.201 | 1100 | >5000 |
29 | I(D)K-Pqa-RHYLNLVTRQRY | 0.43 | 0.078 | >5000 | >5000 |
30 | (D)IK-Pqa-RHYLNLVTRQRY | 0.22 | 0.099 | >5000 | >5000 |
31 | IK-Pqa-RHYLNLVTRQR(N-甲基)Y | 11.8 | 2.6 | >5000 | >5000 |
32 | IK-Pqa-RHYLNLVTRQ(N-甲基)RY | 18.9 | 0.417 | >5000 | >5000 |
33 | IK-Pqa-RHYLNLVT(N-甲基)RQRY | 30.6 | 13.5 | >5000 | >5000 |
34 | IK-Pqa-RHYLNLV(N-甲基)TRQRY | 78.6 | 89 | >5000 | >5000 |
35 | IK-Pqa-RHYLNL(N-甲基)VTRQRY | 44.4 | 42 | >5000 | >5000 |
36 | IK-Pqa-RHYLN(N-甲基)LVTRQRY | 103 | 12 | >5000 | >5000 |
37 | IK-Pqa-RHY(N-甲基)LNLVTRQRY | 782 | 168 | >5000 | >5000 |
38 | IK-Pqa-RH(N-甲基)YLNLVTRQRY | 1.2 | 11.7 | >5000 | >5000 |
39 | IK-Pqa-R(N-甲基)HYLNLVTRQRY | 41.9 | 1.488 | 3800 | >5000 |
40 | IK-Pqa-(N-甲基)RHYLNLVTRQRY | 4.4 | 0.218 | 1600 | >5000 |
41 | I(N-甲基)K-Pqa-RHYLNLVTRQRY | 0.614 | 0.19 | 834 | >5000 |
42 | (N-甲基)IK-Pqa-RHYLNLVTRQRY | 0.799 | 0.12 | 327 | >5000 |
43 | INle-Pqa-RHYLNLVTRQRY | 0.89 | 0.096 | 430 | >5000 |
44 | Ac-INle-Pqa-RHYLNLVTRQRY | 6.1 | 0.338 | 760 | >5000 |
45 | Ac-INle-Pqa-FHYLNLVTRQRY | 19.3 | 2.74 | >5000 | >5000 |
46 | IK-Pqa-RHWLNLVTRQRY | 6.1 | 0.103 | 252 | >5000 |
47 | IK-Pqa-AHWLNLVTRQRY | 17.05 | 0.547 | 1100 | >5000 |
48 | Ac-INle-Pqa-RHYLNLVTRQR(D)Y | 107 | 2.2 | 2020 | >5000 |
49 | Ac-INle-Pqa -RHYLNLVTRQR(N-甲基)Y | 113 | 3.6 | 4200 | >5000 |
50 | Ac-INle-Pqa-RHYLys(28)NLVAsp(32)RQRY(环Lys-Asp) | 92.4 | 33.48 | >5000 | >5000 |
51 | IK-Cms-RHYLNLVTRQRY | 4.91 | 0.1 | >5000 | >5000 |
52 | IKG-Cms-RHYLNLVTRQRY | 4.16 | 0.085 | >5000 | >5000 |
53 | Ac-INle-Cms-RHYLys(28)NLVAsp(32)RQRY(环Lys-Asp) | 146 | 32.25 | >5000 | >5000 |
54 | Ac-INle-Pqa-RHTicLNLVTRQRY | 163 | 45 | >5000 | >5000 |
55 | Ac-INle-Pqa-RHBipLNLVTRQRY | 24.7 | 3.72 | 561 | >5000 |
56 | Ac-INle-Pqa-RHDipLNLVTRQRY | 33.5 | 1.21 | 1516 | >5000 |
57 | Ac-INle-Pqa-RH(1)NalLNLVTRQRY | 13 | 1.36 | 701 | >5000 |
58 | Ac-INle-Pqa-RH(2)NalLNLVTRQRY | 12.3 | 2.68 | 870 | >5000 |
59 | Ac-INle-Pqa-RH(3.4,5三氟Phe)LNLVTRQRY | 13.8 | 1.34 | 1089 | >5000 |
60 | Ac-INle-Pqa-RH(2,3.4,5,6五氟Phe)LNLVTRQRY | 14.2 | 2.13 | 832 | >5000 |
61 | Ac-INle-Pqa-R(4-MeOApc)YLNLVTRQRY | 11.9 | 7.8 | >5000 | >5000 |
62 | Ac-INle-Pqa-R(3-Pal)YLNLVTRQRY | 5.6 | 1.78 | 2022 | >5000 |
63 | Ac-INle-Pqa-R(4-Pal)YLNLVTRQRY | 4.97 | 0.099 | >5000 | >5000 |
64 | Ac-INle-Pqa-(3,4,5三氟Phe)HYLNLVTRQRY | 46 | 1.74 | >5000 | >5000 |
65 | Ac-INle-Pqa-(2,3,4,5,6五氟Phe)HYLNLVTRQRY | 134 | 9.37 | >5000 | >5000 |
66 | Ac-Aib-Nle-Pqa-RHYLNLVTRQRT | 8.9 | 0.38 | 3329 | >5000 |
67 | Ac1-1-Aic-Nle-Pqa-RHYLNLVTRQRT | 8.8 | 0.64 | 1654 | >5000 |
68 | Ac1-1-Aic-Nle-Pqa-RHYLNLVTRQRT | 6 | 1 | 2646 | >5000 |
69 | Ac-2-2Aic-Nle-Pqa-RHYLNLVTRQRT | 8.2 | 0.45 | >5000 | >5000 |
70 | Ac-Ach-Nle-Pqa-RHYLNLVTRQRT | 7.1 | 0.57 | >5000 | >5000 |
71 | Ac-Acp-Nle-Pqa-RHYLNLVTRQRT | 8.7 | 0.303 | >5000 | >5000 |
72 | H-INle-Pqa-RHYLNLVTRQRY | 0.89 | 0.096 | 450 | >5000 |
73 | (PEG-10,000)INle-Pqa-RHYLNLVTRQRY | 7.4 | 45 | ||
74 | (PEG-30,000)INle-Pqa-RHYLNLVTRQRY | 15.4 | 79 |
应当理解,本发明不局限于以上所述的本发明的具体实施方案,因为可以进行具体实施方案的改变并且仍落入后附权利要求的范围内。
实施例A
可以以常规方式制备含有下列组分的薄膜包衣片剂:
成分
每片
核:
式(I)的化合物 10.0mg 200.0mg
微晶纤维素 23.5mg 43.5mg
无水乳糖 60.0mg 70.0mg
聚乙烯吡咯烷酮K30 12.5mg 15.0mg
淀粉羟乙酸钠 12.5mg 17.0mg
硬脂酸镁 1.5mg 4.5mg
(核重) 120.0mg 350.0mg
薄膜包衣:
羟丙基甲基纤维素 3.5mg 7.0mg
聚乙二醇6000 0.8mg 1.6mg
滑石 1.3mg 2.6mg
氧化铁(Iron oxyde)(黄) 0.8mg 1.6mg
二氧化钛 0.8mg 1.6mg
筛分活性成分,与微晶纤维素混和,将混合物与聚乙烯吡咯烷酮的水溶液制粒。将颗粒与淀粉羟乙酸钠和硬脂酸镁混和,压制分别获得120或350mg的核心。将核心用上述薄膜包衣的水溶液/悬浮液包衣。
实施例B
可以以常规方式制备含有下列成分的胶囊:
成分 每胶囊
式(I)化合物 25.0mg
乳糖 150.0mg
玉米淀粉 20.0mg
滑石 5.0mg
筛分各组分并混合和填充到2#胶囊中。
实施例C
注射液可以具有下列组成:
式(I)的化合物 3.0mg
聚乙二醇400 150.0mg
乙酸 适量加至pH5.0
注射液用水 加至1.0ml
将活性成分溶解在聚乙二醇400和注射用水(部分)混和物中。通过乙酸将pH调节至5.0。通过加入残余量的水将体积调节至1.0ml。将溶液过滤,使用适当超额装入小瓶中并灭菌。
实施例D
可以以常规方式制备含有下列成分的软明胶胶囊:
胶囊内容物
式(I)化合物 5.0mg
黄蜡 8.0mg
氢化大豆油 8.0mg
部分氢化植物油 34.0mg
大豆油 110.0mg
胶囊内容物重量 165.0mg
明胶胶囊
明胶 75.0mg
甘油85% 32.0mg
Karion 83 8.0mg(干物质)
二氧化钛 0.4mg
氧化铁黄 1.1mg
将活性成分溶解在其它成分的温热熔融体中,将混合物填充到适当尺寸的软明胶胶囊中。按照通常方法处理填充的软明胶胶囊。
实施例E
可以以常规方式制备含有下列成分的小药囊:
式(I)化合物 50.0mg
乳糖,细粉 1015.0mg
微晶纤维素(AVICEL PH102) 1400.0mg
羧甲基纤维素钠 14.0mg
聚乙烯吡咯烷酮K30 10.0mg
硬脂酸镁 10.0mg
调味添加剂 1.0mg
将活性成分与乳糖、微晶纤维素和羧甲基纤维素钠混和,与聚乙烯吡咯烷酮在水中的混合物一起制粒。将颗粒与硬脂酸镁和调味添加剂混和并装入小药囊。
序列表
<110>霍夫曼-拉罗奇有限公司
<120>神经肽-2受体(Y2R)激动剂及其应用
<130>22849
<140>60/644,840
<141>2005-01-18
<160>42
<170>PatentIn Ver 3.3
<210>1
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>1
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>2
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>2
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>3
<211>36
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>3
Tyr Pro Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu
Glu
1 5 10 15
Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val
Thr
20 25 30
Arg Gln Arg Tyr
35
<210>4
<211>34
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>4
Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu
Asn
1 5 10 15
Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg
Gln
20 25 30
Arg Tyr
<210>5
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>5
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>6
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>6
Arg His Tyr Leu Asn Leu Val Thr Arg Ala Arg Tyr
1 5 10
<210>7
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>7
Arg His Tyr Leu Asn Leu Val Ala Arg Gln Arg Tyr
1 5 10
<210>8
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>8
Arg His Tyr Leu Asn Leu Ala Thr Arg Gln Arg Tyr
1 5 10
<210>9
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>9
Arg His Tyr Leu Asn Ala Val Thr Arg Gln Arg Tyr
1 5 10
<210>10
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>10
Arg His Tyr Leu Ala Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>11
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>11
Arg His Tyr Ala Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>12
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>12
Arg His Ala Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>13
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>13
Arg Ala Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>14
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>14
Ala His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>15
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(12)
<223>(NMe)Tyr
<220>
<223>C-末端酰胺化
<400>15
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>16
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(11)
<223>(NMe)Arg
<220>
<223>C-末端酰胺化
<400>16
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>17
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(9)
<223>(NMe)Arg
<220>
<223>C-末端酰胺化
<400>17
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>18
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(8)
<223>(NMe)Thr
<220>
<223>C-末端酰胺化
<400>18
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>19
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(7)
<223>(NMe)Val
<220>
<223>C-末端酰胺化
<400>19
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>20
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(6)
<223>(NMe)Leu
<220>
<223>C-末端酰胺化
<400>20
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>21
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(4)
<223>(NMe)Leu
<220>
<223>C-末端酰胺化
<400>21
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>22
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>(NMe)Tyr
<220>
<223>C-末端酰胺化
<400>22
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>23
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(2)
<223>(NMe)His
<220>
<223>C-末端酰胺化
<400>23
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>24
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(1)
<223>(NMe)Arg
<220>
<223>C-末端酰胺化
<400>24
Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>25
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>25
Phe His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>26
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>26
Arg His Trp Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>27
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<223>C-末端酰胺化
<400>27
Ala His Trp Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>28
<211>12
<212>PRT
<213>人工序列
<220>人工序列描述:合成肽
<223>
<220>
<223>残基4和8之间的环桥
<220>
<223>C-末端酰胺化
<400>28
Arg His Tyr Lys Asn Leu Val Asp Arg Gln Arg Tyr
1 5 10
<210>29
<211>8
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(1)
<223>Asn(Trt)
<220>
<221>MOD_RES
<222>(4)
<223>Asp(2Pip)
<220>
<221>MOD_RES
<222>(5)
<223>Arg(Pmc)
<220>
<221>MOD_RES
<222>(6)
<223>Gln(Trt)
<220>
<221>MOD_RES
<222>(7)
<223>Arg(Pmc)
<220>
<221>MOD_RES
<222>(8)
<223>Tyr(OBut)
<400>29
Asn Leu Val Asp Arg Gln Arg Tyr
1 5
<210>30
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(1)
<223>Arg(Pmc)
<220>
<221>MOD_RES
<222>(2)
<223>His(Trt)
<220>
<221>MOD_RES
<222>(3)
<223>Tyr(OBut)
<220>
<221>MOD_RES
<222>(5)
<223>Asn(Trt)
<220>
<221>MOD_RES
<222>(9)
<223>Arg(Pmc)
<220>
<221>MOD_RES
<222>(10)
<223>Gln(Trt)
<220>
<221>MOD_RES
<222>(11)
<223>Arg(Pmc)
<220>
<221>MOD_RES
<222>(12)
<223>Tyr(OBut)
<400>30
Arg His Tyr Lys Asn Leu Val Asp Arg Gln Arg Tyr
1 5 10
<210>31
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>Tic
<220>
<223>C-末端酰胺化
<400>31
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>32
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>Bip
<220>
<223>C-末端酰胺化
<400>32
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>33
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>Dip
<220>
<223>C-末端酰胺化
<400>33
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>34
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>(1)Nal
<220>
<223>C-末端酰胺化
<400>34
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>35
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>(2)Nal
<220>
<223>C-末端酰胺化
<400>35
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>36
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>(3,4,5Trifluoro Phe)
<220>
<223>C-末端酰胺化
<400>36
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>37
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(3)
<223>(2,3,4,5,6Pentafluoro Phe)
<220>
<223>C-末端酰胺化
<400>37
Arg His Xaa Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>38
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(2)
<223>(4-MeOApc)
<220>
<223>C-末端酰胺化
<400>38
Arg Xaa Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>39
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(2)
<223>(3-Pal)
<220>
<223>C-末端酰胺化
<400>39
Arg Xaa Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>40
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(2)
<223>(4-Pal)
<220>
<223>C-末端酰胺化
<400>40
Arg Xaa Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>41
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(1)
<223>(3,4,5Trifluoro Phe)
<220>
<223>C-末端酰胺化
<400>41
Xaa His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
<210>42
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列描述:合成肽
<220>
<221>MOD_RES
<222>(1)
<223>(2,3,4,5,6Pentafluoro Phe)
<220>
<223>C-末端酰胺化
<400>42
Xaa His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr
1 5 10
Claims (26)
1.式(I)的神经肽-2受体激动剂:
Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2(I)
其中:
X选自由下列各项组成的组:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨基甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,
Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,
R1是Ile,Ala,(D)Ile,N-甲基Ile,Aib,1-1Aic,2-2Aic,Ach或Acp,
R2是Lys,Ala,(D)Lys,NMelys,Nle或(Lys-Gly),
R3是Arg,Ala,(D)Arg,N-甲基Arg,Phe,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,
R4是His,Ala,(D)His,N-甲基His,4-MeOApc,3-Pal或4-Pal,
R5是Tyr,Ala,(D)Tyr,N-甲基Tyr,Trp,Tic,Bip,Dip,(1)Nal,(2)Nal,3,4,5-三氟Phe或2,3,4,5,6-五氟Phe,
R6是Leu,Ala,(D)Leu或N-甲基Leu,
R7是Asn,Ala或(D)Asn,
R8是Leu,Ala,(D)Leu或N-甲基Leu,
R9是Val,Ala,(D)Val或N-甲基Val,
R10是Thr,Ala或N-甲基Thr,
R11是Arg,(D)Arg或N-甲基Arg,
R12是Gln或Ala,
R13是Arg,(D)Arg或N-甲基Arg,和
R14是Tyr,(D)Tyr或N-甲基Tyr,或其药用盐。
2.根据权利要求1的神经肽-2受体激动剂,其中X是Pqa。
3.根据权利要求1的神经肽-2受体激动剂,其中X是Cms。
4.根据权利要求1的神经肽-2受体激动剂,其中Y是(C1-C6)烷基部分。
5.式(II)的神经肽-2受体激动剂:
Y-R1-R2-X-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(II)
其中:
X是选自由下列各项组成的组的部分:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨基甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,
Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,
R1是Ile,Ala,(D)Ile,N-甲基Ile,Aib,1-1Aic,2-2Aic,Ach或Acp,和
R2是Lys,Ala,(D)Lys,NMelys,Nle或(Lys-Gly),或其药用盐。
6.根据权利要求5的神经肽-2受体激动剂,其中X是Pqa。
7.根据权利要求5的神经肽-2受体激动剂,其中X是Cms。
8.式(III)的神经肽-2受体激动剂:
Y-Ile-Lys-X-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(III)
其中:
X选自由下列各项组成的组:N-哌嗪-1-基-4(3H)-喹唑啉酮-3-乙酸(Pqa),N-(5-O-羧甲基)-5-羟色胺(Cms),4-(2-氨基甲基)-6-二苯并呋喃丙酸,4-(1-哌啶-4-基)-丁酸和4-(2-氨基乙基)-1-羧甲基哌嗪,和
Y是H,取代或未取代的烷基,取代或未取代的低级烷基,取代或未取代的芳基,取代或未取代的烷氧基或聚乙二醇部分,或其药用盐。
9.根据权利要求8的神经肽-2受体激动剂,其中X是Pqa。
10.根据权利要求8的神经肽-2受体激动剂,其中X是Cms。
11.根据权利要求1至10中任何一项的神经肽-2受体激动剂,其选自由下列各项组成的组:
IK-Pqa-RHYLNLVTRQRY,
Ac-IK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRARY,
IK-Pqa-RHYLNLVARQRY,
IK-Pqa-RHYLNLATRQRY,
IK-Pqa-RHYLNAVTRQRY,
IK-Pqa-RHYLALVTRQRY,
IK-Pqa-RHYANLVTRQRY,
IK-Pqa-RHALNLVTRQRY,
IK-Pqa-RAYLNLVTRQRY,
IK-Pqa-AHYLNLVTRQRY,
IA-Pqa-RHYLNLVTRQRY,
Ac-IA-Pqa-RHYLNLVTRQRY,
AK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRQR(D)Y,
IK-Pqa-RHYLNLVTRQ(D)RY,
IK-Pqa-RHYLNLVT(D)RQRY,
IK-Pqa-RHYLNL(D)VTRQRY,
IK-Pqa-RHYLN(D)LVTRQRY,
IK-Pqa-RHYL(D)NLVTRQRY,
IK-Pqa-RHY(D)LNLVTRQRY,
IK-Pqa-RH(D)YLNLVTRQRY,
IK-Pqa-R(D)HYLNLVTRQRY,
IK-Pqa-(D)RHYLNLVTRQRY,
I(D)K-Pqa-RHYLNLVTRQRY,
(D)IK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRQR(N-甲基)Y,
IK-Pqa-RHYLNLVTRQ(N-甲基)RY,
IK-Pqa-RHYLNLVT(N-甲基)RQRY,
IK-Pqa-RHYLNLV(N-甲基)TRQRY,
IK-Pqa-RHYLNL(N-甲基)VTRQRY,
IK-Pqa-RHYLN(N-甲基)LVTRQRY,
IK-Pqa-RHY(N-甲基)LNLVTRQRY,
IK-Pqa-RH(N-甲基)YLNLVTRQRY,
IK-Pqa-R(N-甲基)HYLNLVTRQRY,
IK-Pqa-(N-甲基)RHYLNLVTRQRY,
I(N-甲基)K-Pqa-RHYLNLVTRQRY,
(N-甲基)IK-Pqa-RHYLNLVTRQRY,
INle-Pqa-RHYLNLVTRQRY,
Ac-INle-Pqa-RHYLNLVTRQRY,
Ac-INle-Pqa-FHYLNLVTRQRY,
IK-Pqa-RHWLNLVTRQRY,
IK-Pqa-AHWLNLVTRQRY,
Ac-INle-Pqa-RHYLNLVTRQR(D)Y,
Ac-INle-Pqa-RHYLNLVTRQR(N-甲基)Y,
Ac-INle-Pqa-RHYLys(28)NLVAsp(32)RQRY(环Lys-Asp),
IK-Cms-RHYLNLVTRQRY,
IKG-Cms-RHYLNLVTRQRY,
Ac-INle-Cms-RHYLys(28)NLVAsp(32)RQRY(环Lys-Asp),
Ac-INle-Pqa-RHTicLNLVTRQRY,
Ac-INle-Pqa-RHBipLNLVTRQRY,
Ac-INle-Pqa-RHDipLNLVTRQRY,
Ac-INle-Pqa-RH(1)NalLNLVTRQRY,
Ac-INle-Pqa-RH(2)NalLNLVTRQRY,
Ac-INle-Pqa-RH(3,4,5三氟Phe)LNLVTRQRY,
Ac-INle-Pqa-RH(2,3,4,5,6五氟Phe)LNLVTRQRY,
Ac-INle-Pqa-R(4-MeOApc)YLNLVTRQRY,
Ac-INle-Pqa-R(3-Pal)YLNLVTRQRY,
Ac-INle-Pqa-R(4-Pal)YLNLVTRQRY,
Ac-INle-Pqa-(3,4,5三氟Phe)HYLNLVTRQRY,
Ac-INle-Pqa-(2,3,4,5,6五氟Phe)HYLNLVTRQRY,
Ac-Aib-Nle-Pqa-RHYLNLVTRQRT,
Ac1-1-Aic-Nle-Pqa-RHYLNLVTRQRT,
Ac1-1-Aic-Nle-Pqa-RHYLNLVTRQRT,
Ac-2-2Aic-Nle-Pqa-RHYLNLVTRQRT,
Ac-Ach-Nle-Pqa-RHYLNLVTRQRT,
Ac-Acp-Nle-Pqa-RHYLNLVTRQRT,
H-INle-Pqa-RHYLNLVTRQRY,
(PEG-10,000)INle-Pqa-RHYLNLVTRQRY,和
(PEG-30,000)INle-Pqa-RHYLNLVTRQRY。
12.根据权利要求1至11中任何一项的神经肽-2受体激动剂,其选自由下列各项组成的组:
IK-Pqa-RHYLNLVTRQRY,
Ac-IK-Pqa-RHYLNLVTRQRY,
IK-Pqa-RHYLNLVTRQR(N-甲基)Y,
IK-Pqa-RHYLNLVTRQ(N-甲基)RY,
INle-Pqa-RHYLNLVTRQRY,
Ac-INle-Pqa-RHYLNLVTRQRY,和
(PEG-30,000)INle-Pqa-RHYLNLVTRQRY。
13.神经肽-2受体激动剂,其包含PYY3-36衍生物,该衍生物的氨基酸残基5-24被长度为约8至约11埃的部分所替代。
14.根据权利要求13的神经肽-2受体激动剂,其中所述部分长度是约9至约11埃。
15.根据权利要求14的神经肽-2受体激动剂,其中所述部分长度是约9至约10埃。
16.根据权利要求15的神经肽-2受体激动剂,其中所述部分长度是约8至约10埃。
17.根据权利要求16的神经肽-2受体激动剂,其中所述部分长度是约8至约9埃。
18.药物组合物,其含有根据权利要求1-17中任何一项的化合物和药用载体和/或佐剂。
19.根据权利要求1-17中任何一项的化合物,其用作治疗活性物质。
20.根据权利要求1-17中任何一项的化合物,其用作治疗活性物质,用于治疗和/或预防受神经肽-2受体激动剂调节的疾病。
21.一种用于治疗和/或预防性治疗受神经肽-2受体激动剂调节的疾病的方法、特别是用于治疗和/或预防性治疗肥胖症的方法,该方法包括向人或动物施用根据权利要求1-17中任何一项的化合物。
22.根据权利要求1-17中任何一项的化合物在治疗和/或预防性治疗受神经肽-2受体激动剂调节的疾病中的应用。
23.根据权利要求1-17中任何一项的化合物在治疗和/或预防性治疗肥胖症中的应用。
24.根据权利要求1-17中任何一项的化合物在制备用于治疗和/或预防性治疗受神经肽-2受体激动剂调节的疾病的药物中的应用。
25.根据权利要求1-17中任何一项的化合物在制备用于治疗和/或预防性治疗肥胖症的药物中的应用。
26.以上定义的本发明。
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CN114641486A (zh) * | 2019-10-03 | 2022-06-17 | 庞培法布拉大学 | 用于减少cb1受体激动剂的副作用的肽化合物 |
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CA2872213A1 (en) | 2012-06-13 | 2013-12-19 | F. Hoffmann-La Roche Ag | New diazaspirocycloalkane and azaspirocycloalkane |
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AR095079A1 (es) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo |
SI3068421T1 (sl) | 2013-11-15 | 2019-08-30 | Novo Nordisk A/S | Selektivne spojine PYY in njihova uporaba |
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CN105764905B (zh) | 2013-11-26 | 2019-06-07 | 豪夫迈·罗氏有限公司 | 新的八氢-环丁二烯并[1,2-c;3,4-c’]二吡咯-2基 |
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HUE046820T2 (hu) | 2014-03-26 | 2020-03-30 | Hoffmann La Roche | Biciklusos vegyületek autotaxin (ATX) és lizofoszfatidsav (LPA) termelésgátlókként |
MA41898A (fr) | 2015-04-10 | 2018-02-13 | Hoffmann La Roche | Dérivés de quinazolinone bicyclique |
BR112017025108A2 (pt) | 2015-06-12 | 2018-07-31 | Novo Nordisk As | compostos seletivos de pyy e usos dos mesmos |
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CA2991615A1 (en) | 2015-09-24 | 2017-03-30 | F. Hoffmann-La Roche Ag | Bicyclic compounds as atx inhibitors |
JP6846414B2 (ja) | 2015-09-24 | 2021-03-24 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Atx阻害剤としての二環式化合物 |
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CN102202681A (zh) * | 2008-11-05 | 2011-09-28 | 霍夫曼-拉罗奇有限公司 | 神经肽-2受体(y-2r)激动剂及其用途 |
CN114641486A (zh) * | 2019-10-03 | 2022-06-17 | 庞培法布拉大学 | 用于减少cb1受体激动剂的副作用的肽化合物 |
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TWI309653B (en) | 2009-05-11 |
US20060160742A1 (en) | 2006-07-20 |
CA2594423A1 (en) | 2006-07-27 |
AU2006207659A1 (en) | 2006-07-27 |
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