Local anaesthetic procaine derivatives protect rat against diabetic nephropathy via inhibition of DPP‐4, inflammation and oxidative stress

Abstract

AbstractDiabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine‐embedded thiazole‐pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)‐4, −8, and − 9 enzyme subtypes, where they selectively and potently inhibit DPP‐4 as compared to other subtypes. The top three ranked DPP‐4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF‐ĸB transcription. Among these three, compound 8i was identified as the most potent NF‐ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin‐induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF‐α, IL‐1β and IL‐6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine‐embedded thiazole‐pyrazole compounds as a novel class of agent against diabetic nephropathy.