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。

公开(公告)号：US4721775A

公开(公告)日：1988-01-26

申请号：US771546

申请日：1985-08-26

申请人： Karl Folkers ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

发明人： Karl Folkers ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

IPC分类号： A61K38/00 ,  C07K7/23 ,  C07K7/20

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

摘要： The chemical structure of the luteinizing hormone releasing hormone (LHRH) was elucidatd in 1971. Since then, a very large number of international investigators synthesized more than 100 monosubstituted and about 14 disubstituted analogs of LHRH. All of these analogs were synthesized from natural amino acids having the L-configuration. Not one of these approximately 114 analogs showed agonist activity equivalent to that of LHRH. Two of the 114 were about 60% as active, and neither one has had any utility. We have investigated the six individual L-amino acids which occur in positions 5, 7, and 8 of the four naturally occurring LHRH's which exist in porcine/ovine, salmon, and chicken tissue. There are a total of 16 peptides with these structural features, and we have discovered that not only one but five of these peptides are not only equivalent in certain assays in activity to LHRH, but that two of the five are surprisingly superior to LHRH in activity, and that two of the five have a unique and unpredictable dissociation of activity for the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). These five peptides are:A. p-Glu His Trp Ser His Gly Leu Arg Pro Gly-NH.sub.2,B. p-Glu His Trp Ser His Gly Trp Arg Pro Gly-NH.sub.2,C. p-Glu His Trp Ser His Gly Trp Gln Pro Gly-NH.sub.2,D. p-Glu His Trp Ser His Gly Trp Leu Pro Gly-NH.sub.2,E. p-Glu His Trp Ser Tyr Gly Trp Arg Pro Gly-NH.sub.2,Peptide C might be the naturally occurring as FSHRH, because of its dissociated release of LH and FSH. The discovery for the first time of decapeptides with L-amino acids equal to or more potent than LHRH was based on about 14 years of background. Our new peptides are particularly useful in medical fields for pituitary stimulation and inhibition, for enhancement or inhibition of fertility in humans and animals, for the therapy of hormone-dependent tumors, for special effects on sexual behavior in humans and animals, and for design of new categories of superagonists and antagonists. Extrapituitary effects by these new peptides may be observed on the central nervous system or reproductive organs of humans and animals that are different from those of LHRH. The latter will be especially true if some of these new peptides are found to be native peptides such as FSH-RH or the LHRH-like peptides that have been detected in the gonads that are yet to be identified. The reason for believing this projection is possible is that some of these peptides have high or unique LH and FSH releasing activity in the LHRH radioreceptor assay, as exemplified by the biological activities of peptide C.

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。