{"title":"LHRH agonists.","authors":"K W Funk, J Greer, A L Adjei","doi":"10.1007/0-306-47384-4_8","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_8","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1998-01-01DOI: 10.1093/humrep/3.suppl_1.2
K. Funk, J. Greer, A. Adjei
{"title":"LHRH agonists.","authors":"K. Funk, J. Greer, A. Adjei","doi":"10.1093/humrep/3.suppl_1.2","DOIUrl":"https://doi.org/10.1093/humrep/3.suppl_1.2","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73682116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1998-01-01DOI: 10.1007/0-306-47384-4_25
M E Hadley, V J Hruby, J Blanchard, R T Dorr, N Levine, B V Dawson, F al-Obeidi, T K Sawyer
{"title":"Discovery and development of novel melanogenic drugs. Melanotan-I and -II.","authors":"M E Hadley, V J Hruby, J Blanchard, R T Dorr, N Levine, B V Dawson, F al-Obeidi, T K Sawyer","doi":"10.1007/0-306-47384-4_25","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_25","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_25","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20674264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
After almost two decades, the research on LHRH antagonists has produced a number of decapeptides that are currently in clinical studies. The structures of these antagonists, unlike the agonists, differ substantially from that of LHRH. Five of the ten amino acids are unnatural and of D configuration. The structural combination of a hydrophobic N-terminus (residues 1, 2, and 3) and a basic/hydrophilic C-terminus (residues 6 and 8) was thought to be responsible for some HR reactions encountered with the second generation of LHRH antagonists. This side effect was greatly reduced by substituting the appropriate combination of amino acids at positions 5, 6, and 8. The next hurdle in the drug development of LHRH antagonists was solubility and aggregation. In the case of A-75998, water solubility was improved by 12- to 25-fold via substitution of NMeTyr at position 5. However, based on DLS analysis, the aqueous solutions still contained some large aggregates that were not visible to the naked eye. This formation of aggregates was eliminated on formulating A-75998 in Encapsin. In men, a single s.c. dose of 2 mg of A-75998 suppressed T to the castrate levels for over 30 hr. Other LHRH antagonists including ganirelix and cetrorelix are also in phase I/II clinical studies. Clinical studies with cetrorelix in prostate cancer; in vitro fertilization, and benign prostate hypotrophy have been reported.
经过近二十年的研究，LHRH拮抗剂已经产生了许多目前处于临床研究中的十肽。与激动剂不同，这些拮抗剂的结构与LHRH有很大的不同。十种氨基酸中有五种是非天然的D型氨基酸。疏水n端(残基1、2和3)和碱性/亲水性c端(残基6和8)的结构组合被认为是第二代LHRH拮抗剂遇到的一些HR反应的原因。通过替换位置5、6和8的氨基酸的适当组合，这种副作用大大减少。LHRH拮抗剂药物开发的下一个障碍是溶解度和聚集性。在A-75998的情况下，通过在5位取代NMeTyr，水溶性提高了12- 25倍。然而，根据DLS分析，水溶液中仍含有一些肉眼不可见的大聚集体。在Encapsin中配制A-75998时消除了这种聚集体的形成。在男性中，单次s.c剂量2mg a -75998将T抑制到去势水平超过30小时。其他LHRH拮抗剂包括ganirelix和cetrorelix也处于I/II期临床研究中。头孢瑞克治疗前列腺癌的临床研究体外受精和良性前列腺萎缩也有报道。
{"title":"LHRH antagonists.","authors":"F Haviv, E N Bush, J Knittle, J Greer","doi":"10.1007/0-306-47384-4_7","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_7","url":null,"abstract":"<p><p>After almost two decades, the research on LHRH antagonists has produced a number of decapeptides that are currently in clinical studies. The structures of these antagonists, unlike the agonists, differ substantially from that of LHRH. Five of the ten amino acids are unnatural and of D configuration. The structural combination of a hydrophobic N-terminus (residues 1, 2, and 3) and a basic/hydrophilic C-terminus (residues 6 and 8) was thought to be responsible for some HR reactions encountered with the second generation of LHRH antagonists. This side effect was greatly reduced by substituting the appropriate combination of amino acids at positions 5, 6, and 8. The next hurdle in the drug development of LHRH antagonists was solubility and aggregation. In the case of A-75998, water solubility was improved by 12- to 25-fold via substitution of NMeTyr at position 5. However, based on DLS analysis, the aqueous solutions still contained some large aggregates that were not visible to the naked eye. This formation of aggregates was eliminated on formulating A-75998 in Encapsin. In men, a single s.c. dose of 2 mg of A-75998 suppressed T to the castrate levels for over 30 hr. Other LHRH antagonists including ganirelix and cetrorelix are also in phase I/II clinical studies. Clinical studies with cetrorelix in prostate cancer; in vitro fertilization, and benign prostate hypotrophy have been reported.</p>","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1998-01-01DOI: 10.1007/0-306-47384-4_10
G E Padbury, G L Zipp, F J Schwende, Z Zhao, K A Koeplinger, K T Chong, T J Raub, S Thaisrivongs
{"title":"Factors impacting the delivery of therapeutic levels of pyrone-based HIV protease inhibitors.","authors":"G E Padbury, G L Zipp, F J Schwende, Z Zhao, K A Koeplinger, K T Chong, T J Raub, S Thaisrivongs","doi":"10.1007/0-306-47384-4_10","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_10","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1998-01-01DOI: 10.1007/0-306-47384-4_11
J H Lin, D Ostovic, J P Vacca
{"title":"The integration of medicinal chemistry, drug metabolism, and pharmaceutical research and development in drug discovery and development. The story of Crixivan, an HIV protease inhibitor.","authors":"J H Lin, D Ostovic, J P Vacca","doi":"10.1007/0-306-47384-4_11","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_11","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1998-01-01DOI: 10.1007/0-306-47384-4_23
A A Patchett, R G Smith, M J Wyvratt
{"title":"Orally active growth hormone secretagogues.","authors":"A A Patchett, R G Smith, M J Wyvratt","doi":"10.1007/0-306-47384-4_23","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_23","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_23","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20674262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Renin inhibitors.","authors":"S H Rosenberg, H D Kleinert","doi":"10.1007/0-306-47384-4_2","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_2","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1998-01-01DOI: 10.1007/0-306-47384-4_17
S V Frye, H N Bramson, D J Hermann, F W Lee, A K Sinhababu, G Tian
{"title":"Discovery and development of GG745, a potent inhibitor of both isozymes of 5 alpha-reductase.","authors":"S V Frye, H N Bramson, D J Hermann, F W Lee, A K Sinhababu, G Tian","doi":"10.1007/0-306-47384-4_17","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_17","url":null,"abstract":"","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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