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）： Stampidine [STAMP]，[STV-5 '-[p-bromophenyl methoxyalaninyl phosphate]]是一种新型的司他夫定（STV/d4 T）的芳基磷酸酯衍生物，司他夫定是一种嘧啶核苷类似物，用于治疗HIV感染。STAMP是具有基因型和表型耐药的耐药HIV- 1株的有效抑制剂。STAMP对9株HIV-1非B包膜亚型临床分离株的抗病毒效力是STV/d4 T的100倍，是齐多夫定（ZDV/AZT）的2倍。STAMP抑制了20个基因型和表型核苷类似物耐药（NRTI）和6个非核苷抑制剂（NNRTI）耐药的HIV-1分离株在亚纳摩尔至低纳摩尔浓度下的体外复制。在Hu-PBL-SCID小鼠中，口服STAMP对NRTI耐药临床HIV-1分离株BR/92/019表现出显著的剂量依赖性体内抗HIV活性。在小鼠、大鼠、猫和狗中口服给予配制的GMP级STAMP（25-100 mg/kg/天）硬明胶胶囊后进行的STAMP药代动力学和毒性研究显示有利的药代动力学。在高达500 mg/kg的剂量水平下，STAMP治疗与任何临床或实验室毒性证据无关。在狗和猫中以50或100 mg/kg剂量水平口服给药后，达到了高于其IC 50值的STAMP >4-log的治疗浓度。STAMP对具有基因型和/或表型NRTI或NNRTI抗性以及非B包膜亚型的主要临床HIV-1分离株的体外效力以及其在HIV感染的Hu-PBL SCID小鼠中的体内抗HIV活性和在狗和猫中的有利药代动力学证明了进一步开发这种有前途的新NRTI化合物，以用于可能的临床用途，包括治疗初治和治疗经验丰富的HIV-1。1感染者。我们现在提出的研究，旨在评估的安全性和有效性的STAMP对猫免疫缺陷病毒（FIV）感染的家猫，一个既定的模型HIV-1感染的man. The第一阶段的建议的目标是：（i）评估STAMP的抗逆转录病毒活性在慢性FIV感染的猫;和（ii）评估STAMP的家猫的毒性。我们将检验我们的假设，即用STAMP口服治疗FIV感染的猫可以产生治疗反应而没有副作用。STAMP的进一步开发可能为临床应用于未经治疗和有治疗经验的HIV-1感染者提供重要数据。