IKKβ inhibitors(inhibitor of nuclear factor kappa B kinase subunit beta inhibitors), NFKB1 modulators(nuclear factor kappa B subunit 1 modulators), PAI-1 inhibitors(Plasminogen activator inhibitor 1 inhibitors)

Therapeutic Areas

Congenital DisordersEndocrinology and Metabolic DiseaseEye Diseases+ [2]

Active Indication

Inactive Indication

Pulmonary Disease, Chronic Obstructive

Originator Organization

IMMD, Inc.

Active Organization

IMMD, Inc.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Clinical Trials associated with IMD-1041

NCT00883584

/ Unknown statusPhase 2

A Phase IIa, Proof of Concept Study to Evaluate the Reduction in Inflammatory Biomarkers and Assess Airway Function Following Administration of IMD-1041 in Patients With Chronic Obstructive Pulmonary Disease (COPD)

COPD is a lung disease in which the lung is damaged, making it hard to breathe. In COPD, the airways/tubes that carry air in and out of the lungs are partly obstructed, making it difficult to get air in and out. COPD gets gradually worse over time. At the moment there is no cure for COPD. The best way to slow the disease is to stop smoking. Current medications are used to alleviate shortness of breath and cough, and to treat infections of the lungs that can worsen COPD.
Institute of Medicinal Molecular Design, Inc. (IMMD), a Japanese Drug Discovery Company is developing a compound code named IMD-1041. IMD-1041 is an investigational drug, meaning it is not yet on the market. It is an IKKb inhibitor developed for the treatment of COPD. Unlike most other medications used for COPD currently, IMD-1041 is in capsule form and needs to be taken twice a day. It is also unlike all other drugs in use because it treats the underlying cause of the symptoms.
The purpose of this study is to see if IMD-1041 has the ability to reduce inflammatory derived symptoms and airway remodelling (changes) by looking at certain changes in chemical levels in the blood and sputum (phlegm).

Start Date01 Jul 2008

Sponsor / Collaborator-

EUCTR2007-000190-28-GB

/ Not yet recruitingNot Applicable

A Single Centre, Double-blind, Randomised Study To Investigate a Single Oral Dose of IMD-1041 in A Nasal Allergen Challenge (NAC) Model

Start Date22 Mar 2007

Sponsor / Collaborator-

100 Clinical Results associated with IMD-1041

100 Translational Medicine associated with IMD-1041

100 Patents (Medical) associated with IMD-1041

Literatures (Medical) associated with IMD-1041

15 Oct 2014·Current medicinal chemistryQ2 · MEDICINE

Recent Advances in the Structure-Based and Ligand-Based Design of IKKβ Inhibitors as Anti-inflammation and Anti-cancer Agents

Q2 · MEDICINE

Review

Author: You, Qi-Dong ; Jiang, Zheng-Yu ; Sun, Hao-Peng ; Huang, Jing-Jie ; Zhang, Xiao-Jin ; Chu, Hong-Xi

NF-κB is a significant transcription factor that regulates the expression of various pro-survival genes. IKK is a crucial protein kinase that activates NF-κB translocating from cytoplasm to nucleus for DNA binding. It is composed of three subunits, IKKα, IKKβ, IKKγ (NEMO), where IKKα and IKKβ are catalytic subunits, and IKKγ is the regulatory subunit. Many diseases, such as Hodgkin's disease, Hepatitis-associated hepatocellular carcinoma, colorectal cancer, prostate cancer, rheumatoid arthritis and inflammatory bowel disease, are related to IKK and NF-κB. So far, various IKK inhibitors targeting the ATP binding site have been identified through high throughput screening, rational design or in silico methods, however, only three of them (CHS-828, EB-1627 and IMD-1041) have been under clinical studies, indicating the strategy for the design of IKK inhibitors need to be reinspected. Besides ATP-competitive inhibitors, several other inhibitors have also been disclosed recently, which provide novel concepts to the discovery of IKK inhibitors. In this review, we focus on two parts: 1) the chemotypes and binding patterns of the traditional ATP-competitive IKK inhibitors; 2) novel strategies for the identification of non-ATP-competitive IKK inhibitors as NF-κB modulators. Through these discussions we hope to present inspirations for the development of new IKK inhibitors.

15 Dec 2012·American journal of physiology. Heart and circulatory physiologyQ2 · MEDICINE

Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice

Q2 · MEDICINE

Article

Author: Nagai, Ryozo ; Itai, Akiko ; Hirata, Yasunobu ; Ogawa, Masahito ; Sekinishi, Asuka ; Tanaka, Tetsu ; Suzuki, Jun-ichi ; Isobe, Mitsuaki

Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-κB is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-κB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-κB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IκB via inhibition of IκB kinase-β. IMD-1041 (100 mg·kg−1·day−1) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65-positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC-treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-κB activation.

01 Jan 2012·Molecular vision

Amelioration of endotoxin-induced uveitis treated with an IκB kinase β inhibitor in rats.

Article

Author: Ohno, Shigeaki ; Noda, Kousuke ; Mizutani, Miho ; Namba, Kenichi ; Ando, Ryo ; Itai, Akiko ; Kitaichi, Nobuyoshi ; Dong, Zhenyu ; Lennikov, Anton ; Fujikawa, Tomoyuki ; Kinoshita, Satoshi ; Fukuhara, Junichi ; Ishida, Susumu

PURPOSE:

Endotoxin-induced uveitis (EIU) is an animal model for acute ocular inflammation. Several substances play major roles in the development of inflammatory changes in EIU, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. These inflammatory cytokines trigger the degradation of IκB by activating IκB kinases (IKKs). Released nuclear factor kappaB (NFκB) subsequently translocates to the nucleus, where NFκB expresses its proinflammatory function. IMD-0354, N-(3,5-Bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide, selectively inhibits IKKβ, particularly when induced by proinflammatory cytokines, such as TNF-α and IL-1β. In the present study, we examined whether IKKβ inhibition has therapeutic effects on EIU by using IMD-0354 and its prodrug IMD-1041.

METHODS:

Six-week-old male Lewis rats were used. EIU was induced with subcutaneous injections of 200 μg of lipopolysaccharide (LPS) from Escherichia coli that had been diluted in 0.1 ml of phosphate-buffered saline. IMD-0354 was administered intraperitoneally at 30, 10, 3, or 0 mg/kg, suspended in 1.0 ml of 0.5% carboxymethyl cellulose sodium. The prodrug IMD-1041 (100 mg/kg) was also administered orally. The rats were euthanized 24 h after LPS injection, and EIU severity was evaluated histologically. The number of infiltrating cells and the protein, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) concentrations in the aqueous humor were determined. TNF-α and MCP-1 concentrations were quantified with enzyme-linked immunosorbent assay. Eye sections were also stained with anti-NFκB and phosphorylated I-κBα antibodies.

RESULTS:

The number of infiltrating cells in aqueous humor was 53.6±9.8×10(5), 72.5±17.0×10(5), 127.25±32.0×10(5), and 132.0±25.0×10(5) cells/ml in rats treated with 30, 10, 3, or 0 mg/kg of IMD-0354, respectively. The total protein concentrations of aqueous humor were 92.6±3.1 mg/ml, 101.5±6.8 mg/ml, 112.6±1.9 mg/ml, and 117.33±1.8 mg/ml in rats treated with 30, 10, 3, and 0 mg/kg of IMD-0354, respectively. Infiltrating cells and protein concentrations were significantly decreased by treatment with IMD-0354 (p<0.01). IMD-0354 treatment significantly reduced the concentration of TNF-α (p<0.05) and MCP-1 (p<0.01) in aqueous humor. The number of NFκB positive nuclei was reduced when treated with IMD-0354. Furthermore, IMD-0354-treated EIU rats showed only background levels of phosphorylated I-κBα; however, it was strongly expressed in the iris-ciliary body cell cytoplasm of the IMD-0354 untreated EIU rats. Oral administration of IMD-1041 also decreased the cell number (p<0.01) and protein concentration (p<0.05) of aqueous humor in EIU.

CONCLUSIONS:

Acute uveitis was ameliorated by inhibition of IKKβ in rats. IMD-0354 and its prodrug IMD-1041 seem to be promising candidates for treating intraocular inflammation/uveitis.

News (Medical) associated with IMD-1041

07 Oct 2022

·www.worldpharmanews.com

Repurposing existing drugs to fight new COVID-19 variants

Michigan State University (MSU) researchers are using big data and AI to identify current drugs that could be applied to treat new COVID-19 variants. Finding new ways to treat the novel coronavirus and its ever-changing variants has been a challenge for researchers, especially when the traditional drug development and discovery process can take years. A Michigan State University researcher and his team are taking a hi-tech approach to determine whether drugs already on the market can pull double duty in treating new COVID variants. "The COVID-19 virus is a challenge because it continues to evolve," said Bin Chen, an associate professor in the College of Human Medicine. "By using artificial intelligence and really large data sets, we can repurpose old drugs for new uses." Chen built an international team of researchers with expertise on topics ranging from biology to computer science to tackle this challenge. First, Chen and his team turned to publicly available databases to mine for the unique coronavirus gene expression signatures from 1,700 host transcriptomic profiles that came from patient tissues, cell cultures and mouse models. These signatures revealed the biology shared by COVID-19 and its variants. With the viruss signature and knowing which genes need to be suppressed and which genes need to be activated, the team was able to use a computer program to screen a drug library consisting of FDA-approved or investigational drugs to find candidates that could correct the expression of signature genes and further inhibit the coronavirus from replicating. Chen and his team discovered one novel candidate, IMD-0354, a drug that passed phase I clinical trials for the treatment of atopic dermatitis. A group in Korea later observed that it was 90-fold more effective against six COVID-19 variants than remdesivir, the first drug approved to treat COVID-19. The team further found that IMD-0354 inhibited the virus from copying itself by boosting the immune response pathways in the host cells. Based on the information learned, the researchers studied a prodrug of IMD-0354 called IMD-1041. A prodrug is an inactive substance that is metabolized within the body to create an active drug. "IMD-1041 is even more promising as it is orally available and has been investigated for chronic obstructive pulmonary disease, a group of lung diseases that block airflow and make it difficult to breathe," Chen said. "Because the structure of IMD-1041 is undisclosed, we are developing a new artificial intelligence platform to design novel compounds that hopefully could be tested and evaluated in more advanced animal models." Xing J, Shankar R, Ko M, Zhang K, Zhang S, Drelich A, Paithankar S, Chekalin E, Chua MS, Rajasekaran S, Kent Tseng CT, Zheng M, Kim S, Chen B. Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants. iScience. 2022 Oct 21;25(10):105068. doi: 10.1016/j.isci.2022.105068

100 Deals associated with IMD-1041

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Disease, Chronic Obstructive	Phase 2	United Kingdom	-	01 Jul 2008
Glaucoma	Clinical	Japan	IMMD, Inc.	14 Apr 2020
Diabetes Mellitus	Clinical	Japan	IMMD, Inc.	06 Apr 2020
Age Related Macular Degeneration	Preclinical	Japan	IMMD, Inc.	30 Jan 2022
Diabetes Complications	Preclinical	Japan	IMMD, Inc.	30 Jan 2022
Glaucoma, Neovascular	Preclinical	Japan	IMMD, Inc.	30 Jan 2022
Pulmonary Fibrosis	Preclinical	Japan	IMMD, Inc.	30 Jan 2022

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