Hydrogen sulfide (H2S) has been proposed as a gaseous signaling molecule along with nitric oxide and carbon monoxide (Olson (2011) American Journal of Physiology—Regulatory, Integrative and Comparative Physiology 301, R297-R312). A number of studies examined therapeutic potential of H2S-donating compounds and H2S gas itself for a number of animal models of human disease and injury including ischemic brain injury (Caliendo et al. (2010) J Med Chem 53, 6275-6286; Predmore et al. (2010) Journal of Cardiovascular Translational Research 3, 487-498).
Gaseous H2S, however, may be difficult to be used clinically because of its characteristic odor and toxicity at high concentrations (Olson (2011) American Journal of Physiology—Regulatory, Integrative and Comparative Physiology 301, R297-R312; Reiffenstein et al. (1992) Annu Rev Pharmacol Toxicol 32, 109-134). Sodium sulfide (Na2S) and sodium hydrosulfide (NaHS) have been used as H2S donor compounds in the majority of experimental studies (Caliendo et al. (2010) J Med Chem 53, 6275-6286; Predmore et al. (2010) Journal of Cardiovascular Translational Research 3, 487-498). However, because the half-lives of these sulfide salts are very short in biological fluid, plasma sulfide levels rapidly increase after bolus administration of Na2S or NaHS and then return to baseline instantaneously (DeLeon et al. (2012) Anal Biochem 421, 203-207). To sustain “physiological” levels of sulfide in circulation after bolus administration, many slow-releasing H2S donor compounds, including ACS48, have been developed (Caliendo et al. (2010) J Med Chem 53, 6275-6286; Lee et al. (2010) J Biol Chem 285, 17318-17328).
While it has been reported that low and physiological levels of H2S protect neurons, H2S also exhibits neurotoxicity especially at high concentrations (Reiffenstein et al. (1992) Annu Rev Pharmacol Toxicol 32, 109-134). Some investigators have suggested that H2S-induced neurotoxicity may be mediated via enhancement of N-methyl-D-aspartate (NMDA) receptor activity (Chen et al. (2011) J Cell Physiol 226, 1308-1322; Qu et al. (2006) Stroke 37, 889-893; Cheung et al. (2007) Neuropharmacology 53, 505-514), because toxicity of H2S was abolished by NMDA receptor antagonists in vitro and in vivo (Qu et al. (2006) Stroke 37, 889-893; Cheung et al. (2007) Neuropharmacology 53, 505-514). Based on these observations, it would be desirable to deliver H2S specifically to the central nervous system with a hybrid NMDA receptor antagonist that is capable of slowly releasing H2S in circulation to treat neurodegenerative diseases.
USPTO Backgrounds
USPTO Backgrounds