HI-443 as a Potent Anti-HIV Agent

HI-443 作为有效的抗 HIV 药物

• 批准号: 6549566
• 负责人: BARBARA WAURZYNIAK
• 金额: $ 10万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549566
• 关键词: SCID mouse; antiAIDS agent; antiviral agents; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; oral administration; pharmacokinetics; reverse transcriptase inhibitors; thiophenes; thiourea

DESCRIPTION (provided by applicant): Combination antiretroviral therapy has become the standard of care for patients with human immunodeficiency virus (HIV) infection in the United States. Unfortunately, emergence of drug resistance hampers the long-term success of anti-retroviral treatment regimens. HI-443 is a rationally designed novel anti-HIV compound with potent activity against NNRTI-resistant HIV- 1. (US Patent Serial Number: 6,124,324). The primary goal of our ongoing research is to establish effective methods aimed at improving its oral bioavailability and develop a clinically applicable solid dosage formulation of HI-443. Recently, we developed 3 candidate formulations of HI-443 with good oral bioavailability. We are now proposing studies aimed at evaluating the toxicity profile of these 3 formulations in mice and examining their anti-HIV activity in a SCID mouse model of human AIDS. Under SPECIFIC AIM 1, we will study the toxicity profile of HI-443-F1, HI-443-F2, and HI-443-F3 in mice. We hypothesize that none of the 3 formulations of HI-443 will cause acute, subacute, or chronic toxicity at the proposed dose levels. Under SPECIFIC AIM 2, we will study the in vivo anti-HIV activity of HI-443-F1, HI-443-F2, and HI-443-F3 in a S C D mouse model of human AIDS. We hypothesize that HI-443-F3 will exhibit potent anti-HIV activity in Hu-PBL-SCID mice at nontoxic dose levels. After completion of this Phase I project, we will propose additional preclinical toxicity, pharmacokinetics, and efficacy studies in a Phase II application. The successful accomplishment of the goals may provide the basis for a new treatment strategy for multidrug resistant HIV-1.

描述（由申请人提供）：在美国，联合抗逆转录病毒治疗已成为人类免疫缺陷病毒（HIV）感染患者的标准治疗方案。不幸的是，耐药性的出现阻碍了抗逆转录病毒治疗方案的长期成功。HI-443是一种合理设计的新型抗HIV化合物，对耐nnrti的HIV- 1具有较强的抗活性。（美国专利序列号：6,124,324）。我们正在进行的研究的主要目标是建立有效的方法，旨在提高其口服生物利用度，并开发临床适用的HI-443固体剂量配方。最近，我们开发了3种具有良好口服生物利用度的HI-443候选制剂。目前，我们正在研究这三种制剂在小鼠体内的毒性，并在人类艾滋病SCID小鼠模型中检测它们的抗hiv活性。在SPECIFIC AIM 1下，我们将研究HI-443-F1、HI-443-F2和HI-443-F3对小鼠的毒性。我们假设在建议的剂量水平下，HI-443的3种配方都不会引起急性、亚急性或慢性毒性。在SPECIFIC AIM 2下，我们将研究HI-443-F1、HI-443-F2和HI-443-F3在人艾滋病小鼠S - C - D模型中的体内抗hiv活性。我们假设在无毒剂量水平下，HI-443-F3将在Hu-PBL-SCID小鼠中表现出有效的抗hiv活性。在I期项目完成后，我们将在II期申请中提出额外的临床前毒性、药代动力学和疗效研究。这些目标的成功实现可能为多药耐药HIV-1的新治疗策略提供基础。

项目成果

In vivo pharmacokinetics and toxicity of a novel hydrophilic oral formulation of the potent non-nucleoside reverse transcriptase inhibitor compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443).

强效非核苷逆转录酶抑制剂化合物 N-[2-(2-噻吩)乙基]-N-[2-(5-溴吡啶基)]-硫脲的新型亲水性口服制剂的体内药代动力学和毒性（

• DOI: 10.1055/s-0031-1296608
• 发表时间: 2007
• 期刊: Arzneimittel-Forschung
• 作者: Uckun,FatihM;Tibbles,Heather;Erbeck,Douglas;Venkatachalam,TaracadK;Qazi,Sanjive
• 通讯作者: Qazi,Sanjive

Improved oral bioavailability of anti-HIV agent N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443) in a novel lipophilic formulation.

新型亲脂制剂中的抗 HIV 药物 N-[2-(2-噻吩)乙基]-N-[2-(5-溴吡啶基)]-硫脲 (HI-443) 提高了口服生物利用度。

• DOI: 10.1055/s-0031-1296600
• 发表时间: 2007
• 期刊: Arzneimittel-Forschung
• 作者: Uckun,FatihM;Erbeck,Douglas;Tibbles,Heather;Qazi,Sanjive;Venkatachalam,TaracadK
• 通讯作者: Venkatachalam,TaracadK