ABSTRACT
Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.
Subject(s)
Inflammatory Bowel Diseases/drug therapy , Isoindoles/chemistry , Receptors, CCR/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Chemistry Techniques, Synthetic , Chemotaxis/drug effects , Colitis/chemically induced , Colitis/drug therapy , Disease Models, Animal , Humans , Isoindoles/administration & dosage , Isoindoles/pharmacokinetics , Male , Mice, Inbred C57BL , Receptors, CCR/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
Goldthioglucose induces in mice a significant increase in body weight, glucose, insulin and lipid levels. Treatment with 250 mg/kg of methanol and ethyl acetate extracts of Zingiber officinale for 8 weeks produces significant reduction in body weight, glucose, insulin and lipid levels as compared to obese control mice. The reduction in elevated glucose along with elevated insulin levels indicates that the treatment with Z. officinale improves insulin sensitivity.
Subject(s)
Obesity/drug therapy , Phytotherapy , Zingiber officinale/chemistry , Acetates/chemistry , Animals , Aurothioglucose/administration & dosage , Aurothioglucose/toxicity , Blood Glucose/drug effects , Body Weight/drug effects , Female , Insulin/blood , Lipids/blood , Methanol/chemistry , Mice , Obesity/chemically induced , Plant Extracts/pharmacology , Plant Extracts/therapeutic useABSTRACT
Fructose supplementation produced cardinal features of Syndrome-X including significant elevations in seum cholesterol, triglyceride, glucose and insulin and also in body weight. While treatment with methanolic extract of dried rhizomes of Zingiber officinale produced a significant reduction in fructose induced elevation in lipid levels, bodyweight, hyperglycemia and hyperinsulinemia, treatment with ethyl acetate extract of Z officinale did not poduce any significant change in either of the last two parameters. However, it produced a significant reduction in elevated lipid levels and body weight The concentration of 6-gingerol was found to be higher in methanolic extract and less in ethyl acetate extract. The results suggest that the methanolic extract of Z officinale produces better effects as compared to ethyl acetate extract in fructose induced hyperlipidemia associated with insulin resistance. The extent of activity appears to be dependent on the concentration of 6-gingerol present in the extracts.
