Discovery of 3-[(4,5,7-Trifluorobenzothiazol-2-yl)methyl]indole-N-acetic Acid (Lidorestat) and Congeners as Highly Potent and Selective Inhibitors of Aldose Reductase for Treatment of Chronic Diabetic Complications

1区 · 医学

Article

作者: Gunn, David E. ; Sredy, Janet ; Jacot, Jorge L. ; Geraci, Leo S. ; Mitschler, Andre ; Jones, J. Howard ; Van Zandt, Michael C. ; DiCioccio, A. Thomas ; Podjarny, Alberto D. ; Petrova, Tatiana ; Jones, Michael L. ; Sawicki, Diane R.

Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).

1999-06-01·Emerging Therapeutic Targets

Emerging therapeutics for diabetic retinopathy: potential therapies for the new millennium

作者: Sredy, Janet ; Jacot, Jorge L.

A review with 234 referencesProspective early intervention at the preproliferative stages, prospective therapy for the proliferative stage:retinal vascularization, and challenges ahead were discussed.

Substituted indolealkanoic acids as novel aldose reductase inhibitors.

作者: Jones, J. Howard ; Jones, Michael Lee ; Sredy, Janet ; Van Zandt, Michael C. ; Lavoie, Danny J. ; Podjarny, Alberto D. ; Gunn, David ; Sawicki, Diane ; Howard, Eduardo

Aldose reductase (hALR2), an essential component of the polyol pathway, has long been identified as a target for therapeutic intervention in the development of chronic diabetic complications.To date, however, many potent aldose reductase inhibitors (ARIs) have been found to inhibit aldehyde reductase (hALR1), a related enzyme involved in the detoxification of reactive aldehydes.Recent work in our group has led to the discovery of a series of novel, potent and selective ARIs.The lead compound for this series of substituted indolealkanoic acids inhibits hALR2 with an IC50 of 5 nM, while being 5,400 times less active towards hALR1 (IC50=27,000 nM).The design, synthesis and structure-activity relationships of this series, along with crystal structures of selected enzyme-inhibitor complexes will be discussed.

项与 The Institute for Diabetes Discovery 相关的新闻（医药）

2022-08-02

·BioSpace

Imagine Pharma Awarded Contract from National Institute of Diabetes and Digestive and Kidney Diseases's Integrated Islet Distribution Program to Provide Human Islets

One of only five centers approved to provide human islets for research to academic investigators PITTSBURGH, Aug. 2, 2022 /PRNewswire/ -- Imagine Pharmaceuticals, Inc., a biotechnology company focused on the development of its novel polypeptide (IMG-1) across three distinct platforms: Oral Delivery, Therapeutics, and Regenerative Medicine, announced today that the Integrated Islet Distribution Program (IIDP) has selected it as an approved Islet Isolation Center (IIC). The (IIDP) is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), an institute within the U.S. Department of Health and Human Services' National Institutes of Health. The award is effective as of August 1, 2022. The IIDP is the largest organized effort in the world to provide high-quality human islet preparations to the diabetes research community to advance discoveries, and currently supplies over 100 investigators with human islets for their research programs. As human islet preparation requires specialized expertise and costly processes available in very few laboratories, the IIDP enables a coordinated approach to human islet distribution. Imagine Pharma's Islet Center is one of only five IICs currently selected to participate in the IIDP program. Imagine's Islet Center is headed by Dr. Rita Bottino, who brings more than 25 years of experience and knowledge to islet isolation and was recently recognized as one of the top 10 leading experts in Islet of Langerhans transplantation worldwide during the years 2012-2022. Imagine's Islet Center currently supplies human islet cells to some of the leading academic diabetes centers in the country, including Vanderbilt University, University of Florida, and the University of Pittsburgh. "Human islet research is critical to understanding diabetes, and access to high-quality human islets is essential to supporting this research," said Dr. Bottino. "I am very excited that Imagine Pharma has been selected to support the diabetes research community through this award, and am grateful to the NIDDK for the opportunity to help advance diabetes research." "Selection as an approved Islet Isolation Center for the IIDP program is a testament to Imagine Pharma's expertise in this very specialized procedure," said Santiago Pujadas, Co-CEO of Imagine Pharma. "With diabetes as one of our therapeutic areas of interest beyond islet isolation, we are thrilled that we can contribute to ongoing research and potential cures through our ability to provide high-quality human islets for the world's leading research organizations." About the Integrated Islet Distribution Program (IIDP) Created in 2002, the IIDP consists of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Project Scientist and Program Official, an External Scientific Panel, and the Coordinating Center at City of Hope. The IIDP integrates an interactive group of five islet isolation centers to coordinate the distribution of human islets. Since its establishment, the IIDP has placed more than 275 million islets supporting more than 500 unique studies across 12 countries, yielding more than 800 peer-review publications. The program is supported by the Special Statutory Funding Program for Type 1 Diabetes Research and is administered by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Imagine Pharma Islet Center Imagine Pharma's Islet Center provides research-grade human isolated islets, tissue processing and related services to the diabetes research community. The Center currently supplies human islet cells to some of the leading academic diabetes centers in the United States, including Vanderbilt University, University of Florida, Mt. Sinai Icahn School of Medicine in New York, the University of Pittsburgh as well as the Network for Pancreatic Donors with Diabetes (nPOD). In addition to its Islet Isolation Center, Imagine Pharma's Islet Programs include islet consulting services; customized processing of pancreatic organs to provide both tissue biopsies as well as isolated islets; and on demand islet isolation from large mammal pancreatic organs. About Imagine Pharma Imagine Pharma is a biotechnology company focused on the development of its IMG-1 polypeptide. Research and development efforts have led to the development of three distinctive platforms for Oral Delivery, Therapeutics, and Regenerative Medicine, each with first-in-class programs that address multiple disease states in large, underserved markets. Imagine Pharma was recently selected as an approved Islet Isolation Center for the National Institute of Diabetes and Digestive and Kidney Diseases Integrated Islet Distribution Program. Imagine Pharma was founded in 2016 in Pittsburgh, PA. For more information visit: The content in this release is the sole responsibility of the authors and does not necessarily represent the official views or imply endorsement of the National Institutes of Health.

First in Class

100 项与 The Institute for Diabetes Discovery 相关的药物交易

登录后查看更多信息

100 项与 The Institute for Diabetes Discovery 相关的转化医学

登录后查看更多信息