Discovery of Novel Bicyclic Imidazolopyridine-Containing Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Improved Efficacy and Favorable Druggability

Abstract

Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower compared with that of lesinurad. Moreover, 23 exhibited stronger URAT1 inhibition activity (IC50 = 1.36 μM) than lesinurad (IC50 = 5.54 μM). Additionally, 23 showed favorable safety profiles, and no obvious acute toxicity was observed in Kunming mice under a single dose of 1000 mg·kg–1. 23 also achieved excellent pharmacokinetic properties with the oral bioavailability of 59.3%. Overall, all the results indicated that 23 is a promising drug candidate in the treatment of hyperuricemia and gout.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

“…The significant SUA-lowering activity of compound 29 prompted us to investigate its binding mode with URAT1 using the URAT1 homology model constructed in our previous study. 25 As illustrated in Figure 4, 29 exhibited π−π stacking interactions with Phe365 and Phe241 similar to lesinurad. Additionally, 29 formed a hydrogen bond with Gln473 and interacted with Phe364 through a π−π interaction in the predicted binding pocket.…”

“…Ultimately, several drug candidates were obtained, including T7 and TD-3 which exhibited significant SUA-lowering activity in vivo , as well as inhibitory effects on URAT1 in vitro while possessing favorable drug-like properties and safety profiles (Figure ). − …”

Agents for the Treatment of Gout: Current Advances and Future Perspectives

“…Accordingly, compounds (38) were synthesized; the most active of these was compound 38a (DR = 96.1%) (Figure ). …”

“…Accordingly, compounds (38) were synthesized; the most active of these was compound 38a (DR = 96.1%) (Figure 14). 77 In the field of medicinal chemistry, even minimal chemical modifications can result in considerable changes in the inhibitor activity. Therefore, compounds (39) were synthesized by replacing the sulfur atom with the oxygen atom to further explore the SARs of the compounds.…”

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

“…Incorporation of two or more pharmacophores of bioactive scaffolds based on molecular hybridization has been one of the most successful strategies for the discovery of new pesticides and drugs. − For example, flubeneteram, a novel commercial SDHI fungicide approved recently (Figure ), was discovered through pharmacophore-linked fragment virtual screening (PFVS) by the Yang group, − which could be considered as a combination of pyrazole-4-carboxamide and diphenyl ether bioactive scaffolds based on the molecular hybridization strategy. Scaffold hopping, another widely exploited design approach, offers the opportunity to modify known lead compounds to afford novel structures with high potency, low toxicity, and enhanced physicochemical properties. − In this work, in search of novel SDHIs, flubeneteram was used as lead compounds, and we attempted to replace the diphenyl ether scaffold of flubeneteram with extended phenyl diether and aliphatic ether by scaffold hopping (Figure ).…”