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 As 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 (IC 50 1.87 and 2.03 μM, respectively). 17b (IC 50 0.078 μM) and 17 f (IC 50 0.094 μM) inhibited ACE‐1 comparable to perindopril (PER) (IC 50 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.