A hydrogen peroxide responsive prodrug of Keap1-Nrf2 inhibitor for improving oral absorption and selective activation in inflammatory conditions

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

“…To date, several classes of small-molecule inhibitors have been designed to non-covalently inhibit the PPI of the Keap1 Kelch domain and the Nrf2 Neh2 motifs, 20,[23][24][25][26][27][28][29][30][31][32][33] including several recently developed compounds. [34][35][36][37][38][39][40][41][42][43][44][45] However, the Neh2-binding pocket of the Keap1 Kelch domain is large (550-780 Å) and contains multiple arginine residues, thus representing a challenging target for drug development. 14 This is reflected in the reported Keap1-Nrf2 PPI inhibitors, which generally have high molecular weights and contain carboxylic acids leading to poor cell and CNS permeability.…”

A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1–Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury

“…Following the discovery of ML334, several other direct small-molecule antagonists of Keap1–Nrf2 interaction have been reported ( Supplementary Table 1 and Fig. S1 ) [ [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] ], including tetrahydroisoquinoline, 1,4-diaminonaphthalene, and its analogs, phenyl pyrrole, phenyl pyrazole, phenyl triazole, phenyl furan, and miscellaneous scaffolds. However, while some of this small-molecule the Keap1–Nrf2 protein-protein interaction (PPI) inhibitors exhibit nanomolar potency in vitro , they usually possess aliphatic acid groups, such as carboxylic acid ( e.g.…”

“…Although these aliphatic acid groups may play an important role for the recognition and interaction with Keap1 [ 33 ], they may also decrease membrane permeability in cellulo [ 33 ]. Moreover, while some studies have described the use of Keap1-Nrf2 inhibitors for treating APAP-induced liver injury have been reported [ 21 , 38 ], concerns regarding pharmacokinetic parameters and relatively low in vivo efficacy still remain [ 24 ]. Several small-molecule antagonists without aliphatic acid groups have been reported [ 24 , 31 , 32 ], but they are all derived from the 1,4-diaminonaphthalene scaffold and none of these inhibitors, to our knowledge, have been investigated for treating APAP-induced hepatotoxicity in cellulo and in vivo .…”

“…Moreover, while some studies have described the use of Keap1-Nrf2 inhibitors for treating APAP-induced liver injury have been reported [ 21 , 38 ], concerns regarding pharmacokinetic parameters and relatively low in vivo efficacy still remain [ 24 ]. Several small-molecule antagonists without aliphatic acid groups have been reported [ 24 , 31 , 32 ], but they are all derived from the 1,4-diaminonaphthalene scaffold and none of these inhibitors, to our knowledge, have been investigated for treating APAP-induced hepatotoxicity in cellulo and in vivo . Moreover, assessments of toxicity, including organ damage and immunotoxicity, for these compounds are still limited.…”

Synthesis of novel pyrazoline-thiazolidin-4-one hybrids and evaluation their biological activity

“…In this context, the structure modified thiazolidin-4-one and pyrazoline nucleus are prospective molecular platforms for design antioxidants and redoxmodulating agent design [5][6][7][8]. For example, the application of the mentioned scaffolds is an attractive direction for the development of selective modulators of Nrf2 and NF-kB transcription factors, that play a key role in the regulation of cellular responses to oxidative-stress factors and are potential drug targets [9][10][11].…”