Structure–Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury

Abstract

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem without effective drugs. Inhibition of sirtuin 5 (SIRT5) has been confirmed to protect against AKI, suggesting that SIRT5 inhibitors might be a promising therapeutic approach for AKI. Herein, structural optimization was performed on our previous compound 1 (IC 50 = 3.0 μM), and a series of 2,4,5-trisubstituted pyrimidine derivatives have been synthesized. The structure−activity relationship (SAR) analysis led to the discovery of three nanomolar level SIRT5 inhibitors, of which the most potent compound 58 (IC 50 = 310 nM) was demonstrated to be a substratecompetitive and selective inhibitor. Importantly, 58 significantly alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)-and cecal ligation/perforation (CLP)-induced septic AKI mice. Further studies revealed that 58 regulated protein succinylation and the release of proinflammatory cytokines in the kidneys of septic AKI mice. Collectively, these results highlighted that targeting SIRT5 has a therapeutic potential against septic AKI.

Current Trends in Sirtuin Activator and Inhibitor Development

“…Sirt5 is also a recent target of sirtuin inhibitor development [ 133 , 140 , 141 ]. Since glutarylation is a Sirt5 acylation substrate [ 29 ], 3-thioureidopropanoic acid derivatives were developed to competitively inhibit Sirt5 by imitating glutarylated Sirt5 substrates [ 141 ].…”

“…Computational docking predicted that the compounds bind in the Sirt5 acylated substrate binding cleft; kinetic assays supported these predictions by demonstrating competitive inhibition against a fluorogenic Sirt5 succinylated substrate [ 141 ]. Further SAR studies yielded Compound 58 , an acylated substrate-competitive Sirt5 inhibitor with nanomolar potency (IC 50 = 310 nM) and improved selectivity for Sirt5 over Sirt1/3 [ 140 ]. Notably, Compound 58 improved kidney function in two mouse models of sepsis-induced acute kidney injury, though the mechanism by which Sirt5 inhibition exerts kidney-protective effects is unknown [ 140 ].…”

“…Further SAR studies yielded Compound 58 , an acylated substrate-competitive Sirt5 inhibitor with nanomolar potency (IC 50 = 310 nM) and improved selectivity for Sirt5 over Sirt1/3 [ 140 ]. Notably, Compound 58 improved kidney function in two mouse models of sepsis-induced acute kidney injury, though the mechanism by which Sirt5 inhibition exerts kidney-protective effects is unknown [ 140 ]. Screening a 5000-member drug-like compound library coupled with SAR optimization of the pyrazolone-containing hit also produced Sirt5 inhibitor Compound 47 ( Table 2 ), with an IC 50 value of 210 nM and >3800-fold selectivity for Sirt5 over Sirt1/2/3/6 [ 133 ].…”

“…Screening a 5000-member drug-like compound library coupled with SAR optimization of the pyrazolone-containing hit also produced Sirt5 inhibitor Compound 47 ( Table 2 ), with an IC 50 value of 210 nM and >3800-fold selectivity for Sirt5 over Sirt1/2/3/6 [ 133 ]. Like the other reported Sirt5 inhibitors [ 140 , 141 ], Compound 47 was predicted to bind the Sirt5 acylated substrate binding pocket and exhibited competitive inhibition against a Sirt5 succinylated substrate [ 133 ].…”

Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity

“…Efforts to develop potent and specific Sirtuin inhibitors yielded several pharmacological compounds with high potency and specificity, most of which target Sirt1 and −2, and only a few of them target Sirt3, −5, and −6. ,,, The most potent inhibitors are the nonspecific Sirt1/2/3 inhibiting ELT compounds (IC 50 ∼ 3 nM), and only one Sirtuin inhibitor, the Sirt1 inhibitor EX-527 (Selisistat; IC 50 ∼ 100 nM), has so far entered clinical trials. , For Sirt4, however, only nonspecific compounds have been described so far, and most of them show low potency. The physiological pan-Sirtuin inhibitors NAM and NADH inhibit Sirt4 with higher potency than other isoforms (IC 50 values of 13 and ∼126 μM, respectively), but have many additional physiological targets .…”