Stampidine: A Novel Broad-Spectrum Antiviral Agent

Stampidine：一种新型广谱抗病毒药物

• 批准号: 6654784
• 负责人: TARACAD VENKATACHALAM
• 金额: $ 10万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2004-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654784
• 关键词: antiAIDS agent; antiviral agents; cats; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; feline immunodeficiency virus; histopathology; human immunodeficiency virus 1; pharmacokinetics; polymerase chain reaction; reverse transcriptase inhibitors; stavudine

DESCRIPTION (provided by applicant): Stampidine [STAMP], [STV-5'-[p-bromophenyl methoxyalaninyl phosphate] is a novel aryl phosphate derivative of Stavudine (STV/d4T), a pyrimidine nucleoside analogue used in the treatment of HIV infection. STAMP was a potent inhibitor of drug-resistant HIV- 1 strains with genotypic and phenotypic drug resistance. STAMP was 100-fold more potent than STV/d4T and 2-fold more potent than zidovudine (ZDV/AZT) against 9 clinical HIV-1 isolates of non-B envelope subtype. STAMP inhibited the in vitro replication of 20 genotypically and phenotypically nucleoside analogue-resistant (NRTI) and 6 nonnucleoside inhibitor (NNRTI)-resistant HIV-I isolates tested at subnanomolar to low nanomolar concentrations. Orally administered STAMP exhibited significant and dose-dependent in vivo anti-HIV activity against the NRTI-resistant clinical HIV-1 isolate, BR/92/019 in Hu-PBL-SCID mice. Pharmacokinetic and toxicity studies of STAMP conducted in mice, rats, cats, and dogs following oral administration of formulated GMP-grade STAMP (25-100 mg/kg/day) as hard gelatin capsules showed favorable pharmacokinetics. STAMP therapy was not associated with any clinical or laboratory evidence of toxicity at dose levels as high as 500 mg/kg. Therapeutic concentrations of STAMP >4-logs higher than its IC50 value was achieved after oral administration in dogs and cats at the 50 or 100 mg/kg dose levels. The documented in vitro potency of STAMP against primary clinical HIV-1 isolates with genotypic and/or phenotypic NRTI- or NNRTI-resistance as well as non-B envelope subtype together with its in vivo anti-HIV activity in HIV-infected Hu-PBL SCID mice and favorable pharmacokinetics in dogs and cats warrants the further development of this promising new NRTI compound for possible clinical use in both treatment naive and treatment experienced HIV-1 infected persons. We are now proposing studies aimed at evaluating the safety and efficacy of STAMP against the feline immunodeficiency virus (FIV) infection in domestic cats, an established model for HIV-1 infection in man. The goals of this Phase I proposal are: (i) To evaluate the anti-retroviral activity of STAMP in chronically FIV-infected cats; and (ii) To evaluate the toxicity profile of STAMP in domestic cats. We will test our hypothesis that oral treatment of FIV-infected cats with STAMP can lead to therapeutic response without side effects. The further development of STAMP may provide important data for possible clinical use in both treatment naive and treatment experienced HIV-1 infected persons.

描述（由申请人提供）： 斯图丁[Stamp]，[STV-5' - [P-溴苯基甲氧酰磷酸酯]是一种新型的Stavudine（STV/D4T）的新型芳基磷酸衍生物，这是一种用于治疗HIV感染的嘧啶核苷类似物。邮票是具有基因型和表型耐药性的耐药性HIV-1菌株的有效抑制剂。邮票比STV/D4T高100倍，比Zidovudine（ZDV/AZT）对非B信封亚型的9个临床HIV-1分离株高2倍。邮票抑制了20种基因型和表型上核苷类似物（NRTI）和6种非核苷抑制剂（NNRTI）耐药的HIV-I分离株的体外复制。口服邮票在体内抗HIV活性显着且剂量依赖性，对NRTI耐药的临床HIV-1分离株，HU-PBL-SCID小鼠中的BR/92/019。口服配方GMP级邮票（25-100 mg/kg/day）后，在小鼠，大鼠，猫和狗中进行的邮票的药代动力学和毒性研究显示出良好的药代动力学。邮票疗法与剂量水平高达500 mg/kg的任何临床或实验室证据无关。在50或100 mg/kg剂量水平的狗和猫中，在口服口服后达到了高于其IC50值的邮票的治疗浓度。 The documented in vitro potency of STAMP against primary clinical HIV-1 isolates with genotypic and/or phenotypic NRTI- or NNRTI-resistance as well as non-B envelope subtype together with its in vivo anti-HIV activity in HIV-infected Hu-PBL SCID mice and favorable pharmacokinetics in dogs and cats warrants the further development of this promising new NRTI compound for possible clinical use in治疗幼稚和治疗都经历了HIV-1感染的人。现在，我们提出的研究旨在评估邮票对家猫中猫免疫缺陷病毒（FIV）感染的安全性和功效，这是人类中HIV-1感染的既定模型。该阶段I建议的目标是：（i）评估长期感染的猫中邮票的抗逆转录病毒活性； （ii）评估家猫邮票的毒性概况。我们将测试我们的假设，即用邮票对FIV感染的猫进行口服处理可以导致治疗反应而无需副作用。邮票的进一步开发可能会提供重要的数据，以便在治疗和治疗中可能临床使用，并且经历了HIV-1感染的人。