{"title":"杂环多环氨基甲酰基吡啶酮作为 HIV-1 整合酶链转移抑制剂的分子设计和评估。","authors":"Toshiyuki Akiyama , Brian A. Johns , Yoshiyuki Taoda , Hiroshi Yoshida , Teruhiko Taishi , Takashi Kawasuji , Hitoshi Murai , Tomokazu Yoshinaga , Akihiko Sato , Takahiro Seki , Mikiko Koyama , Shigeru Miki , Shinobu Kawauchi-Miki , Akemi Kagitani-Suyama , Tamio Fujiwara","doi":"10.1016/j.bmcl.2024.129902","DOIUrl":null,"url":null,"abstract":"<div><p>Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure–activity studies using these scaffolds resulted in several leads with promising properties.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"111 ","pages":"Article 129902"},"PeriodicalIF":2.5000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors\",\"authors\":\"Toshiyuki Akiyama , Brian A. Johns , Yoshiyuki Taoda , Hiroshi Yoshida , Teruhiko Taishi , Takashi Kawasuji , Hitoshi Murai , Tomokazu Yoshinaga , Akihiko Sato , Takahiro Seki , Mikiko Koyama , Shigeru Miki , Shinobu Kawauchi-Miki , Akemi Kagitani-Suyama , Tamio Fujiwara\",\"doi\":\"10.1016/j.bmcl.2024.129902\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure–activity studies using these scaffolds resulted in several leads with promising properties.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":\"111 \",\"pages\":\"Article 129902\"},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24003044\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24003044","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors
Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure–activity studies using these scaffolds resulted in several leads with promising properties.
期刊介绍:
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.