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    CHRH antagonists with low histamine release
    1.
    发明授权
    CHRH antagonists with low histamine release 失效
    低组胺释放的CHRH拮抗剂

    公开(公告)号：US5470947A

    公开(公告)日：1995-11-28

    申请号：US371552

    申请日：1989-06-26

    申请人： Karl A. Folkers ,  Anders Ljungqvist ,  Dong-Mei Feng ,  Minoru Kubota ,  Pui-Fun L. Tang ,  Cyril Y. Bowers

    发明人： Karl A. Folkers ,  Anders Ljungqvist ,  Dong-Mei Feng ,  Minoru Kubota ,  Pui-Fun L. Tang ,  Cyril Y. Bowers

    IPC分类号： A61K38/04 ,  A61K38/00 ,  A61P15/00 ,  C07K7/06 ,  C07K7/23

    CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S930/13

    摘要： Antide is the decapeptide, N--Ac--D--2--Nal,D--pClPhe, D--3--Pal, Ser,NicLys, D--NicLys, Leu, ILys, Pro, D--Ala,NH.sub.2 which is an antagonist of luteinizing hormone releasing hormone (LHRH). This decapeptide, like others of the present invention, has high antiovulatory activity (AOA) and releases negligible histamine. Antide is scheduled for scale-up, safety testing and evaluation in the experimental primate and in clinical medicine. Numerous other peptides having structures related to Antide were prepared and tested. These peptides had variations primarily in positions 5, 6, 7, and 8. Of these, N--Ac--D--2--Nal, D--pClPhe,D--3--Pal,Ser,PicLys,cis--DpzACAla, Leu,ILys,pro,D--Ala--NH.sub.2 was one of the most potent and had higher antiovulatory activity than Antide, i.e. 73%/0.25 ug and 100%/0.5 ug vs. 36%/0.5 ug and 100%/1.0 ug. Antide showed significant, (p

    摘要翻译： Antide是黄素化拮抗剂的十肽，N-Ac-D-2-Nal，D-pClPhe，D-3-Pal，Ser，NicLys，D-NicLys，Leu，ILys，Pro，D-Ala，NH2 激素释放激素（LHRH）。 这种十肽与本发明的其它物质一样，具有高的抗疟药活性（AOA），释放出可忽略的组胺。 Antide计划在实验灵长类动物和临床医学中进行放大，安全测试和评估。 制备并测试了许多具有与Antide有关的结构的其它肽。 这些肽主要在第5,6,7和8号位置有变化。其中，N-Ac-D-2-Nal，D-pClPhe，D-3-Pal，Ser，PicLys，cis-DpzACAla，Leu，ILys ，pro-D-Ala-NH2是最有效的并且具有比Antide更高的抗肿瘤活性，即73％/ 0.25ug和100％/ 0.5ug，而36％/ 0.5ug和100％/1.0μg。 当在50ng激动剂[D-3-Qal6] -LHRH之前以10μg，44小时的剂量注射时，Antide显示显着的（p <0.001）作用持续时间。 Antide在600ug（73％）和1200μg（100％）下显示口服AOA，水和玉米油口服制剂之间的差异可以忽略不计。

    Effective antagonists of the luteinizing hormone releasing hormone which release negligible histamine
    2.
    发明授权
    Effective antagonists of the luteinizing hormone releasing hormone which release negligible histamine 失效
    促黄体生成激素释放激素的有效拮抗剂释放出可忽略的组胺

    公开(公告)号：US4935491A

    公开(公告)日：1990-06-19

    申请号：US88431

    申请日：1987-08-24

    申请人： Karl Folkers ,  Anders Ljungqvist ,  Dong-Mei Feng ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

    发明人： Karl Folkers ,  Anders Ljungqvist ,  Dong-Mei Feng ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

    IPC分类号： A61K38/04 ,  A61K38/00 ,  A61P15/00 ,  C07K7/06 ,  C07K7/23

    CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S930/13

    摘要： The objective of the research was the achievement of antagonists of the luteinizing hormone releasing hormone (LHRH) which would have adequate antagonistic activity to prevent ovulation, and yet would not have a pronounced structural feature to release a histamine, in vivo. Some existing antagonists of LHRH produced edema of the face and extremities in rats. This recent recognition of the edematogenic and anaphylactoid activities of an antagonist of LHRH necessitated new structural changes if such antagonists were to be considered for potential use as contraceptive agents in the human. Consequently, 57 peptides have been designed, synthesized and bioassayed toward achieving a potent antagonist which releases negligible histamine. Since there was no predictable structural sequence which offered assurance of such achievement, it was necessary to design, synthesize and bioassay a very large number of peptides having diverse structural changes toward ultimately discovering an antagonist with the necessary potency of antiovulatory activity and the necessary negligible release of histamine. Ultimately, this objective was achieved, and this application describes the diverse and unpredictable many positive steps which finally led to the objectives.

    摘要翻译： 研究的目标是实现促黄体激素释放激素（LHRH）的拮抗剂，其具有足够的拮抗活性以防止排卵，并且在体内不具有释放组胺的显着结构特征。 一些现有的LHRH拮抗剂在大鼠中产生了四肢的水肿。 最近对LHRH拮抗剂引起的血液发生和过敏性活性的认识需要新的结构改变，如果这样的拮抗剂被认为可能用作人类的避孕药。 因此，已经设计，合成和生物测定了57种肽，以实现释放可忽略的组胺的有效拮抗剂。 由于没有可预测的结构序列来提供这种成就的保证，所以有必要设计，合成和生物测定大量具有不同结构变化的肽，以最终发现拮抗剂具有必需的抗疟药活性和必需的可忽略的释放 的组胺。 最终，这个目标已经实现，这个应用程序描述了最终导致目标的多样化和不可预测的许多积极步骤。