Sparsentan: First Approval

Syed, Yahiya Y.

doi:10.1007/s40265-023-01864-x

Cited by 19 publications

(6 citation statements)

References 20 publications

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“…The anticancer drug kinase inhibitors quizartinib and tivozanib have been covered in earlier sections. Sparsentan (approved 2/2023) is a first-in-class medication for patients suffering from focal segmental glomerulosclerosis (FSGS). In addition to the isoxazole, sparsentan is also decorated with an unusual oxidized spiro-imidazole nitrogen heterocycle.…”

Section: Us Fda-approved Nitrogen-containing Drugs (January 2013–dece...mentioning

confidence: 99%

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

Marshall,

Federice,

Bell

et al. 2024

J. Med. Chem.

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This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938−2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO 2 ). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycle�82%, compared to 59% from preceding decades�as well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs. ■ SIGNIFICANCEThis Perspective reinforces the significant role nitrogen heterocycles play as diverse tunable structural components of U.S. FDA-approved drugs (2013FDA-approved drugs ( −2023. This follow-up study reveals major increases in 1) the percentage of drugs containing a nitrogen heterocycle, 2) the number of nitrogen heterocycles per drug, and 3) the diversity of nitrogen heterocycles as well as the important roles fluorine and sulfur substituents continue to play. New atoms (B, D, and Si) are also introduced into this arena.

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Section: Us Fda-approved Nitrogen-containing Drugs (January 2013–dece...mentioning

confidence: 99%

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

Marshall,

Federice,

Bell

et al. 2024

J. Med. Chem.

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“…Sparsentan (RE-021, PS433540, DARA-a) is a first-in-class, orally active, dual-acting, selective antagonist of the AT1 receptor and the endothelin type A (ET A ) receptor [ 44 ]. This compound has been in development for the treatment of focal segmental glomerulosclerosis, IgA nephropathy, and other kidney-related conditions [ 45 , 46 , 47 ]. In focal segmental glomerulosclerosis, certain segments of some glomeruli become scarred and damaged, leading to a decrease in their filtering function.…”

Section: Sparsentan (N-(4-((5-(4-(2-carboxyethyl)-1-piperazinyl)-2-me...mentioning

confidence: 99%

Investigating the Impact of Selective Modulators on the Renin–Angiotensin–Aldosterone System: Unraveling Their Off-Target Perturbations of Transmembrane Ionic Currents

Lu,

2023

IJMS

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The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation, electrolyte balance, and overall cardiovascular health. However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na+ channels, was shown to stimulate peak and late components of voltage-gated Na+ current (INa). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late INa directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca2+-activated K+ channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late INa effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late INa along with a slowing of the inactivation time course of the current. However, telmisartan’s presence can also suppress the erg-mediated K+ current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K+ current and the M-type K+ current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding.

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“…Data from the PROTECT study indicated that after 9 months of treatment, sparsentan was able to reduce the urine protein to creatinine ratio (UPCR) to a significantly greater extent than the ARB irbesartan, although long-term data are needed to ascertain whether this translates to long-term renoprotection [103]. The overall safety profile of sparsentan was similar to that of irbesartan, although higher rates of peripheral edema, hypotension, dizziness, and anemia were observed [102,103].…”

Section: Symptom Reduction and Supportive Carementioning

confidence: 99%

“…The second drug approved by the FDA for the treatment of IgAN was the dual en dothelin angiotensin-receptor antagonist sparsentan, which is also indicated for the re duction in proteinuria in adults with primary IgAN at risk of rapid disease progressio [102]. Data from the PROTECT study indicated that after 9 months of treatmen sparsentan was able to reduce the urine protein to creatinine ratio (UPCR) to a signif cantly greater extent than the ARB irbesartan, although long-term data are needed to as certain whether this translates to long-term renoprotection [103].…”

Section: Targeted Treatmentsmentioning

confidence: 99%

A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence

Mathur,

Chan,

et al. 2023

JCM

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A PRoliferation-Inducing Ligand (APRIL), the thirteenth member of the tumor necrosis factor superfamily, plays a key role in the regulation of activated B cells, the survival of long-lived plasma cells, and immunoglobulin (Ig) isotype class switching. Several lines of evidence have implicated APRIL in the pathogenesis of IgA nephropathy (IgAN). Globally, IgAN is the most common primary glomerulonephritis, and it can progress to end-stage kidney disease; yet, disease-modifying treatments for this condition have historically been lacking. The preliminary data in ongoing clinical trials indicate that APRIL inhibition can reduce proteinuria and slow the rate of kidney disease progression by acting at an upstream level in IgAN pathogenesis. In this review, we examine what is known about the physiologic roles of APRIL and evaluate the experimental and epidemiological evidence describing how these normal biologic processes are thought to be subverted in IgAN. The weight of the preclinical, clinical, and genetic data supporting a key role for APRIL in IgAN has galvanized pharmacologic research, and several anti-APRIL drug candidates have now entered clinical development for IgAN. Herein, we present an overview of the clinical results to date. Finally, we explore where more research and evidence are needed to transform potential therapies into clinical benefits for patients with IgAN.

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Sparsentan: First Approval

Cited by 19 publications

References 20 publications

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

Investigating the Impact of Selective Modulators on the Renin–Angiotensin–Aldosterone System: Unraveling Their Off-Target Perturbations of Transmembrane Ionic Currents

A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence

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