Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme‐1/cyclooxygenase‐2 inhibitors: Design, synthesis, anti‐hypertensive, anti‐fibrotic, and anti‐inflammatory

Abstract

AbstractAs a hybrid weapon, two novel series of pyrazoles, 16a‐f and 17a‐f, targeting both COX‐2 and ACE‐1‐N‐domain, were created and their anti‐inflammatory, anti‐hypertensive, and anti‐fibrotic properties were evaluated. In vitro, 17b and 17f showed COX‐2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF‐κB (IC50 1.87 and 2.03 μM, respectively). 17b (IC50 0.078 μM) and 17 f (IC50 0.094 μM) inhibited ACE‐1 comparable to perindopril (PER) (IC50 0.048 μM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF‐κB‐p65 and P38‐MAPK expression by −0.62, −0.22, −0.53, and −0.24 folds, respectively compared to  l‐NAME (−0.34, −0.45 folds decline in NF‐κB‐p65 and P38‐MAPK, respectively). 17b reduced ANG‐II expression which significantly reversed the cardiac histological changes induced by L‐NAME.