Materials and methods for inhibiting mamalian S-nitrosoglutathione reductase
View Patent ↗The current study reports novel inhibitors of s-nitrosoglutathione reductase (GSNOR) identified that specifically inhibit GSNOR among the alcohol dehydrogenases. These inhibitors may bind into the GSNO binding site and inhibit GSNOR at multiple places in its kinetic pathway. These molecules inhibit GSNOR in a dose dependent manner and demonstrate that GSNOR actively regulates the s-nitrosylation of proteins against incoming low molecular weight nitrosothiols. These compounds are useful in method of treatment of diseases such as asthma, chronic obstructive pulmonary disease, heart disease, heart failure, heart attack, hypertension, atherosclerosis, restenosis, impotence, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, septic shock, cardiogenic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, and other inflammatory diseases. These compounds can also be used to diagnose and/or study disease and/or conditions or enzymes involving the s-nitrosylation of proteins.
1. A method of treating an inflammatory disease associated with GSNOR activity, comprising the steps of:
administering to a patient in need thereof a therapeutically effective dose of a compound having a structure:
or pharmaceutically acceptable salt or ester thereof, wherein said inflammatory disease associated with GSNOR activity is selected from the group consisting of: asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung disease due to cystic fibrosis, cystic fibrosis, ulcerative colitis and Crohn's disease.
2. The method according to claim 1 , wherein the therapeutically effective amount of said compound is in the range of about 0.01 mg/kg per of body mass day to about 1000 mg/kg of body mass per day.
3. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt or ester thereof.
4. The method of claim 3 , wherein the inflammatory disease is selected from the group of diseases of the lung consisting of: asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and cystic fibrosis.