Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug-Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis.
Silvia BuaLaura LucariniLaura MicheliMarta MenicattiGianluca BartolucciSilvia SelleriLorenzo Di Cesare MannelliCarla GhelardiniEmanuela MasiniFabrizio CartaPaola GratteriAlessio NocentiniClaudiu T SupuranPublished in: Journal of medicinal chemistry (2019)
Multitarget nonsteroidal anti-inflammatory drug (NSAID)-carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending on the NSAID portion. A selection of derivatives were assayed in vitro to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated that the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative (5c) showed major antihyperalgesic action compared with the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multitarget compounds, which induce markedly improved pain relief compared with the parent NSAIDs.
Keyphrases
- rheumatoid arthritis
- anti inflammatory
- chronic pain
- disease activity
- pain management
- neuropathic pain
- molecular dynamics
- interstitial lung disease
- crispr cas
- oxidative stress
- electronic health record
- adverse drug
- emergency department
- genome editing
- dna binding
- postoperative pain
- idiopathic pulmonary fibrosis
- deep learning