Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers

Abstract

Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxylation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8-to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (C max at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.

Lesinurad – There are More Ways than One of Synthesizing the Drug

“…The t1/2 for isomerization is in excess of 275 days at 100 °C. 9 The (+)-1 isomer is more than three times more active against hURAT1 (IC50 4.4 µM) than (-)-1 (IC50 15.1 µM) and is more metabolically stable in a human recombinant CYP2C9 assay. 4,9 It has been speculated that administration of a single isomer may help overcome side effects such as renal toxicity and serum creatinine elevation 4,5 but no enantiomerically pure form has reached the market, yet.…”

Exploring the Solid-State Landscape of Atropisomers in (±)-Lesinurad: Insights into Crystallographic Analysis, Transformation Behavior, and Dissolution Performance

“…4−7 Although atropisomers significantly impact a compound's pharmacological activity and metabolism, they are often overlooked due to the absence of a stereogenic center. 8,9 Numerous studies have focused on simplifying atropisomerism by symmetrization or eliminating it by promoting rapid interconversion. Conversely, constraining rotation can isolate a specific conformer, offering a novel approach to drug design and development.…”

“…17 evidence suggests that (+)-LES provides enhanced therapeutic efficacy for treating hyperuricemia/gout compared to (−)-LES and the racemic mixture. 9,17 The commercially available drug Zurampic includes a racemic blend of these atropisomers in a 50:50 ratio, which crystallizes into a specific enantiomorphic conglomerate, referred to as form II. 18 Upon isolating the two atropisomers from racemic LES, we discovered that both presented in an amorphous state (Figure S1).…”

“…With advancements in chiral separation technologies and a deepening understanding of chiral drugs, there is an increasing emphasis on how chirality influences the pharmacological activity, toxicity, and metabolic properties of drugs . Axial chirality, a unique form of chirality, arises from steric hindrance or electronic effects that restrict the free rotation around covalent bonds, a phenomenon termed atropisomerism. , As the quest for more compact and structurally intricate compounds progresses in pharmaceutical research, numerous instances of atropisomerism have been identified, highlighting its significance. − Although atropisomers significantly impact a compound’s pharmacological activity and metabolism, they are often overlooked due to the absence of a stereogenic center. , Numerous studies have focused on simplifying atropisomerism by symmetrization or eliminating it by promoting rapid interconversion. Conversely, constraining rotation can isolate a specific conformer, offering a novel approach to drug design and development. , …”

“…Research has shown that (+)-LES and (−)-LES can be separated as distinct conformers from racemic LES, indicating a stable atropisomeric structure that resists interconversion under extreme conditions. , These atropisomers demonstrate stereoselective behavior in clinical pharmacokinetics, metabolism, and URAT1 inhibition potency. Notably, evidence suggests that (+)-LES provides enhanced therapeutic efficacy for treating hyperuricemia/gout compared to (−)-LES and the racemic mixture. , The commercially available drug Zurampic includes a racemic blend of these atropisomers in a 50:50 ratio, which crystallizes into a specific enantiomorphic conglomerate, referred to as form II…”