Development of novel Amadorins for Diabetic Peripheral Neuropathy

开发治疗糖尿病周围神经病变的新型 Amadorins

基本信息

  • 批准号:
    10461055
  • 负责人:
  • 金额:
    $ 37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-19 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Diabetic peripheral neuropathy (DPN) is the most common diabetic complication. DPN is a leading cause for disability due to foot ulceration and amputation, gait disturbance, and fall-related injury. There is no FDA- approved disease modifying treatment for DPN, a condition affecting up to 50% of the estimated 30 million diabetic patients in the US. Neuropathy occurs in patients with both type 1 and type 2 diabetes but the only current recommendation for preventing or slowing progression of neuropathy is to maintain close glycemic control. Multiple drugs are available to treat hyperglycemia itself, but no drugs that treat the pathogenesis of DPN or the other complications have succeeded in advanced clinical trials. Praetego Inc. plans to advance new chemical entities in the class of “Amadorins” for the treatment of DPN pathogenesis. Hyperglycemia is the key common factor linking all diabetic complications. Direct reaction of proteins with glucose leads to formation of so-called advanced glycation endproducts (AGEs). Praetego Inc. and others believe that AGE formation underlies, at least in part, all the major microvascular complications of diabetes. In diabetic patients, these glucose-mediated reactions damage the microvascular blood vessels that nourish nerves, the retina and kidney glomeruli. Our present focus is the preclinical drug development of two novel Amadorin AGE inhibitors that emerged in our Phase I SBIR study. We will advance the drug development of a lead Amadorin candidate, PTG- 630, and, as a de-risking strategy, secondary studies will be carried out on a back-up Amadorin PTG-641, with distinguishing properties from the lead. In our Phase I SBIR grant, we studied the in vitro AGE inhibition potency of several novel Amadorins, and the in vitro and in vivo safety of the most promising candidates, PTG-630 and PTG-640. Both demonstrated the predicted potent AGE inhibition and also exhibited the hoped for improved margin of safety in maximum tolerated dose (MTD) studies and in in vitro off-target screening panels. PTG-630 was the most potent AGE inhibitor and proved safer than our previous lead. We designate it as our lead candidate. PTG-640 demonstrated an extremely high MTD, likely due to limited absorption, and no hits in the in vitro off-target panel screen. However, our preferred back-up is its precursor methyl ester PTG-641. It is deemed the better drug candidate for development: it should hydrolyze in the body to the safe PTG-640, it is a 3-fold stronger AGE inhibitor, and it should have better bioavailability. Thus, in this Phase II STTR we will: (1) characterize and optimize the chemical properties, stability and bioavailability of these two drug candidates, and (2) advance the best forms of these two leads into long-term preclinical efficacy in multiple DPN rodent models of Type 1 and Type 2 diabetes. A key objective will be obtaining central nervous system and small and large fiber measurements that translate to clinical endpoints. Successful completion of this project will determine which of the two preferred candidates to carry further into IND-enabling studies, with sufficient experimental data generated for an early pre-IND FDA meeting.
项目总结

项目成果

期刊论文数量(0)
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RAJA G KHALIFAH其他文献

RAJA G KHALIFAH的其他文献

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{{ truncateString('RAJA G KHALIFAH', 18)}}的其他基金

Amadorins as a Novel Oral Therapeutic for Diabetic Retinopathy
Amadorins 作为糖尿病视网膜病变的新型口服疗法
  • 批准号:
    10601168
  • 财政年份:
    2023
  • 资助金额:
    $ 37万
  • 项目类别:
Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)
Amadorins 用于改善阿尔茨海默病和相关痴呆症 (ADRD)
  • 批准号:
    10704225
  • 财政年份:
    2022
  • 资助金额:
    $ 37万
  • 项目类别:
Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)
Amadorins 用于改善阿尔茨海默病和相关痴呆症 (ADRD)
  • 批准号:
    10819236
  • 财政年份:
    2022
  • 资助金额:
    $ 37万
  • 项目类别:
Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)
Amadorins 用于改善阿尔茨海默病和相关痴呆症 (ADRD)
  • 批准号:
    10546238
  • 财政年份:
    2022
  • 资助金额:
    $ 37万
  • 项目类别:
Development of novel Amadorins for Diabetic Peripheral Neuropathy
开发治疗糖尿病周围神经病变的新型 Amadorins
  • 批准号:
    10250543
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:
Development of novel Amadorins for Diabetic Peripheral Neuropathy
开发治疗糖尿病周围神经病变的新型 Amadorins
  • 批准号:
    10284641
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:
Development of novel Amadorins for Diabetic Peripheral Neuropathy
开发治疗糖尿病周围神经病变的新型 Amadorins
  • 批准号:
    10079227
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:

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