Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.,Journal of Medicinal Chemistry

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Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-21 , DOI: 10.1021/acs.jmedchem.9b01681
Guo Li ₁ , Nicholas A Meanwell ₂ , Mark R Krystal ₃ , David R Langley ₄ , B Narasimhulu Naidu ₂ , Prasanna Sivaprakasam ₄ , Hal Lewis ₅ , Kevin Kish ₅ , Javed A Khan ₅ , Alicia Ng ₆ , George L Trainor ₇ , Christopher Cianci ₃ , Ira B Dicker ₃ , Michael A Walker ₂ , Zeyu Lin ₃ , Tricia Protack ₃ , Linda Discotto ₃ , Susan Jenkins ₈ , Samuel W Gerritz ₁ , Annapurna Pendri ₁

Affiliation

Department of Early Discovery Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, United States.
Department of Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, United States.
Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, United States.
Department of Computer-Aided Drug Design & Molecular Analytics, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543-4000, United States.
Department of Molecular Structure and Design, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543-4000, United States.
Department of Materials Science, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, United States.
Department of Chemistry, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, United States.

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

中文翻译：

发现和优化新型的吡唑并嘧啶作为有效的和口服生物利用的变构HIV-1整合酶抑制剂。

HIV-1感染的护理标准，即高活性抗逆转录病毒疗法（HAART），结合了至少两种药物中的两种或多种药物。即使HAART取得了成功，仍需要具有新颖机制的新药来对抗病毒抗药性，改善依从性并减轻毒性。HIV-1整合酶的活性位点抑制剂在临床上已被证实可用于治疗HIV-1感染。在这里，我们描述了与LEDGF / p75相互作用位点结合并破坏HIV-1成熟所需的整合酶多聚体的结构的HIV-1整合酶的变构抑制剂。开发了一系列基于吡唑并嘧啶的抑制剂，其2-位载体已通过结构导向的化合物设计进行了优化。从而发现了吡唑并嘧啶3，

更新日期：2020-02-21

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