|Categories||Small molecules, anti-inflammatory treatment|
|Development Stage||In-vivo proof of concept|
|Patent Status||Patent application filed|
|Market||Inflammation indications: acute pancreatitis, acute live damage, fatty liver damage, diabetic nephropathy|
Chronic activation of the immune system occurs in a variety of pathological conditions and is associated with the release of pro-inflammatory cytokines, TNF-a, IL-6, IL-1β and an increase in reactive oxygen species (ROS). Although TNF-a antagonists may produce a marked improvement in conditions such as rheumatoid arthritis and ulcerative colitis, they can also cause serious adverse effects.
We have developed a family of indoline derivatives which prevent cytotoxicity induced by ROS and the release of pro-inflammatory cytokines from lipopolysaccharide (LPS) activated macrophages.
- Acute pancreatitis – In a mouse model, 2 mg/kg of the compounds bring about almost complete prevention of rise in serum amylase and TNF-α, reduction by >50% of edema, necrosis and neutrophil infiltration and degradation of IκB-α in the pancreas after 4 h.
- Acute liver damage – In a mouse model of acute liver damage, a dose of 0.25 mg/kg of the compounds brings about a >60% reduction of the increase in serum ALT and liver apoptosis, and reduction from 90% to 20% in the lethality in mice after 72 hr.
- Fatty liver damage – In a fatty liver in-vivo model, 1 mg/kg/day causes significant reduction of the liver/body weight ratio, p<0.01, plasma ALT and liver fat content (oil red).
- Diabetic Nephropathy – In a mouse model of type 1 diabetes, treatment with 0.25 mg/kg bid for 3 months abolishes the damage to the glomerular area and mesangial expansion. One of the compounds decreases the rise in serum and urine glucose, and urine urea (p<0.01), while another one reduces the albumin/creatinine ratio (p<0.01). Both compounds abolish the rise in gene expression of collagen 1 and 3, lipocalin 2 and fibronectin in the kidney. One compound also prevents the rise in TIMP1 and TGFβ
- Some of the compounds are also active through the oral route at about 2-5 times higher doses.
- No adverse effects were seen during a 3-day observation period in mice after the injection of three of the compounds at doses of 25 mg/kg.
- The compounds, which are readily prepared from commercially available compounds, are achiral. They are isolated as water soluble, crystalline salts.
- The compounds are stable for extended periods, both in solid form as well as in aqueous solution.
- These compounds and their biological activities have been patented.
Seeking investment in new company or industrial collaboration for product development and clinical studies.
Prof. Marta Weinstock, Institute for Drug Research, The School of Pharmacy – Institute for Drug Research, Jerusalem, Israel
Prof. Abraham Nudelman, Chemistry Department, Bar Ilan University, Ramat Gan, Israel.
Granted US 9,499,484; Europe 3405454