Development of Hydrogen Sulfide-Releasing Carbonic Anhydrases IX- and XII-Selective Inhibitors with Enhanced Antihyperalgesic Action in a Rat Model of Arthritis

An effective therapeutic approach based on the anti-inflammatory
action of hydrogen sulfide (H2S) and inhibition of carbonic
anhydrases (CAs) IX and XII is proposed here for the management of
arthritis. H2S is a human gasotransmitter that modulates
inflammatory response at low concentrations. Inhibition of CAs IX
and XII can repristinate normal pH in the acidic inflamed synovial
fluid, alleviating arthritis symptoms. We report here the design of
H2S donorCA inhibitor (CAI) hybrid derivatives.
The latter were tested in vitro as inhibitors of human CAs I, II,
IV, IX, and XII, showing a markedly increased inhibition potency/isoform
selectivity compared to the CAI synthetic precursors. The best compounds
demonstrated the ability to consistently release H2S and
produce a potent pain-relieving effect in a rat model of arthritis.
Compound 26 completely reverted the pain state 45 min
after administration with enhanced antihyperalgesic effect in vivo
compared to the single H2S donor, CAI fragment, or their
co-administration.