Лефлуномид

Описание

Leflunomide is an orally-available disease-modifying antirheumatic drug and was launched as Arava in the US for the treatment of rheumatoid arthritis (RA) ; it is the first and only drug to be indicated to slow down structural joint damage of RA, so addressing an unmet medical need.
Leflunomide is prepared in 3 steps from the appropriate acetoacetic anilide using a nitrile oxide- enamine cycloaddition reaction to assemble the isoxazole ring. Leflunomide is a prodrug, being extensively metabolized in vivo into the corresponding 2-cyano-3-hydroxy-2-butenamide resulting from fragmentation of the isoxazole ring. This cyanoenol is actually the active metabolite and several experiments in animals have demonstrated that after oral administration, substantial and sustained levels of this metabolite were delivered to the systemic circulation.
In vitro, Leflunomide’s active metabolite inhibits dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidine nucleotides, probably accounting for its immunosuppressive effect in vivo. Other mechanisms of action such as inhibition of tyrosine kinase and inhibition of responsiveness to interleukin-2 have been proposed. In diverse models of autoimmune or allergic diseases, Leflunornide showed efficacy both prophylactically and therapeutically.

Химические свойства

Off White Crystalline Solid

Использование

By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation and treatment of rheumatoid arthritis and other autoimmune diseases.

Определение

ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-methyl-1,2-oxazole-4-carboxylic acid with the anilino group of 4-(trifluoromethyl)aniline. The prodrug of teriflunomide.

Показания

Leflunomide (Arava) is an isoxazole derivative approved for the treatment of rheumatoid arthritis in 1998. Limited data suggest that it is comparable in efficacy to sulfasalazine and produces fewer adverse effects. It has a faster onset of action (4 weeks) than other DMARDs.

Биологические функции

Leflunomide is inactive, but teriflunomide inhibits pyrimidine de novo synthesis at low therapeutic doses by inhibiting dihydroorotate dehydrogenase (the rate-determining enzyme for the synthesis of UMP), decreasing DNA and RNA synthesis, and arresting the cell proliferation cycle and production of antibodies. The reduction of dihydroorotate to orotate occurs concurrently with the reduction of its cofactor, ubiquinone (coenzyme Q). The inhibition of dihydroorotate dehydrogenase by teriflunomide demonstrates noncompetitive and uncompetitive kinetics. Administration of leflunomide in patients with rheumatoid arthritis results in progressive removal of B cells and down-regulation of the immune process. Teriflunomide not only inhibits B-cell proliferation but also T-cell proliferation, blocking the synthesis of immunosuppressive cytokines. At high therapeutic doses, leflunomide inhibits protein tyrosine kinases.

Общее описание

Leflunomide (Arava), an isoxazole prodrug, is an orally activeDMARD marketed in 1998 for the treatment of RA. Itis well absorbed and extensively metabolized in vivo to itsactive metabolite, 2-cyano-3-hydroxy-2-buteneamide (teriflunomide),resulting from a reductive ring opening of theisoxazole ring. Unlike MTX, teriflunomideblocks T-cell proliferation by inhibiting dihydroorotate dehydrogenase,the rate-limiting enzyme in the de novobiosynthesis of pyrimidine that is believed to be responsiblefor the immunosuppressive properties of leflunomide.For this reason, it is not surprising that leflunomide has avery comparable therapeutic efficacy to the first-lineDMARD, MTX as shown in several extended open clinicaltrials. However, even though leflunomide is well toleratedlike MTX, several cases of toxic neuropathy have beenobserved during its use, thus careful monitoring of the patient’sneurological status during treatment is mandatory.Like MTX, leflunomide is contraindicated in pregnancy orin women considering pregnancy.

Биологическая активность

Immunosuppressant agent. In vitro the active metabolite A77 1726 (RS-61980) inhibits dihydroorotate dehydrogenase (K i = 2.7 μ M) and de novo pyrimidine synthesis in T-cells; blocks lymphocyte cell cycle progression and proliferation. A77 1726 also inhibits anti-CD3/CD28-induced cytokine production in PBMC cells (IC 50 = 21-27 μ g/ml). In vivo reduces inflammation in several animal models of autoimmune disease, arthritis, asthma and graft rejection.

Фармакокине?тика

Leflunomide is a pro-drug that is rapidly and almost completely metabolized (half-life, <60 minutes) following oral administration to teriflunomide, the pharmacologically active α-cyanoenol metabolite. The C3-H of the isoxazole ring is essential for the ring opening to its active metabolite. The reaction is similar to CYP1A2-catalyzed dehydration of aldoximes. The exact mechanism of action of leflunomide in the management of rheumatoid arthritis has not been fully elucidated but appears to principally involve inhibition of B-lymphocyte (B-cell) proliferation, reducing antibody formation. Activated lymphocytes must proliferate and synthesize large quantities of cytokines, requiring increased de novo synthesis of uridine monophosphate (UMP) and other pyrimidine nucleotides for its cell life cycle. Therefore, any substance that reduces the intracellular concentration of pyrimidine nucleotides will affect the growth of these activated cells.

Фармаколо?гия

Leflunomide is a prodrug that is converted to an active malonitrilamide metabolite, A77 1726 (M1). M1 inhibits T-cell proliferation by blocking de novo pyrimidine synthesis and inhibiting the tyrosine kinases that are associated with certain cytokine and growth factor receptors.

Клиническое использование

Leflunomide is a DMARD with anti-inflammatory and immunosuppressive activity used for the management of rheumatoid arthritis. It retards structural damage associated with arthritis in adults who have moderate to severe active rheumatoid arthritis. Leflunomide also is being investigated for use in patients with solid tumors and organ transplant recipients.

Побочные эффекты

Diarrhea occurs in approximately one-third of patients taking this drug; indigestion, nausea, and vomiting occur in about 10%. Other common adverse effects include weight changes, headache, skin rashes, pruritus, and reversible alopecia and hepatic enzyme elevation.Although leflunomide acts as an immunosuppressive, it does not appear to cause significant bone marrow depression.

Меры предосторожности

Leflunomide is teratogenic in animal models; it is absolutelycontraindicated in pregnancy, in women whomay become pregnant, and in breast-feeding women.Because of its long half-life, the M1 metabolite ofleflunomide may remain in the body for up to 2 years;therefore, a drug elimination procedure using cholestyramineshould be used before any attempt at pregnancy.This drug is not recommended for use in children.Caution should be used when administering thisdrug to individuals with renal or hepatic disease, heavyalcohol use, or immunosuppression.
The long half-life of leflunomide must be taken intoaccount to prevent drug interactions. Hepatotoxicity ispossible if leflunomide is given in conjunction with a hepatotoxicagent such as methotrexate or certain NSAIDs.Leflunomide inhibits CYP2C9, the enzyme responsiblefor the metabolism of numerous drugs. Rifampin inducesthe P450 enzyme responsible for converting leflunomide to its M1 metabolite.Cholestyramine enhances the clearanceof leflunomide and its M1 metabolite.