515814-01-4

Voclosporin, a structurally similar analogue of cyclosporin A, is a new type of calcineurin inhibitor. It has been modified to increase its activity by 3-4 times and exhibits a dual and synergistic mechanism. This drug works by blocking the expression of IL-2 and T cell-mediated immune response, stabilizing renal podocytes. Compared to cyclosporin, voclosporin has the advantage of having less impact on cholesterol and triglycerides and a lower risk of diabetes. In February 2021, vorcyclosporine was approved by the FDA for use in combination immunosuppressive regimens in adult patients with active, lupus nephritis.

Voclosporin is a new agent for the treatment of noninfectious uveitis. Uveitis is an inflammatory, putative Th1-mediated autoimmune disease that affects various parts of the eye and is a leading cause of visual loss . Voclosporin, a rationally designed novel calcineurin inhibitor, exhibits a favorable safety profile, a strong correlation between pharmacokinetic and pharmacodynamic response, and a wide therapeutic window.

ChEBI: Voclosporin is a homodetic cyclic peptide.

Voclosporin is approved by the USFDA for the treatment of active lupus nephritis.

Voclosporin (Lupkynis(TM)) is an oral calcineurin inhibitor immunosuppressant that is being developed by Aurinia Pharmaceuticals. In January 2021, based on positive results from the pivotal phases II and III trials, oral voclosporin received its first approval in the USA for use in combination with a background immunosuppressive therapy regimen for adults with active lupus nephritis.

The synthesis of voclosporin begins with the higher intermediate cyclosporin A14.1, a natural product that can be obtained by fermentation. Cyclosporin A14.1 is treated with acetic anhydride, pyridine, and DMAP in dichloromethane to afford acetylcyclosporin A14.2 in good yield. Intermediate 14.2 is then subjected to ozonolysis to afford the oxidative addition product 14.3. Homologation reactions of aldehyde 14.3 with propyne trimethylsilane and bis(cyclopentadienyl)zirconium hydrochloride in the presence of silver perchlorate afford the trans-olefin 14.4. Finally, base-mediated removal of the acetyl group affords voclosporin (14), which is then purified by semi-preparative high pressure liquid chromatography (HPLC).

1. Voclosporin: First Approval DOI: 10.1007/s40265-021-01488-z
2. Voclosporin: A Novel Calcineurin Inhibitor for the Treatment of Lupus Nephritis DOI: 10.1177/10600280221075331