Tamibarotene

BeschreibungTamibarotene, a selective agonist of the retinoic acid receptor, was launched in Japan as an oral treatment for relapsed or refractory acute promyelocytic leukemia (APL). APL is a form of acute myeloid leukemia (AML) characterized by a deficiency in mature blood cells and an excess of immature cells called promyelocytes in the bone marrow and peripheral blood. The current standard of care for APL includes treatment with all-trans-retinoic acid (ATRA), either alone or in combination with chemotherapy. ATRA is a high affinity ligand for two types of nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), each of which has three subtypes (-α, -β, and -γ). Activation of RARα by ATRA causes promyelocytes to differentiate and mature, thereby inhibiting their proliferation and inducing disease remission. Although ATRA is one of the most clinically successful retinoids, its usage is hampered by the high rate of adverse effects, instability, and the appearance of ATRA-resistant leukemia cells.Adverse events included retinoic acid syndrome, hyperleukocytosis, xerosis, cheilitis, hypertriglyceridemia, and hypercholesterolemia; however, these side effects were generally milder than with ATRA, which all patients had received previously. Examination of human samples taken from Phase II and III clinical trials revealed that fecal excretion was the major elimination route, and the metabolism of tamibarotene occurred primarily through hydroxylation and taurine conjugation. In vitro, the plasma protein binding of tamibarotene is shown to be ＞98% in rats, dogs, and humans. Tamibarotene is synthesized from 5,5,8,8-tetramethyl-5,6,7, 8-tetrahydronaphthalene in a four-step sequence consisting of regioselective nitration in the 2-position, reduction of the nitro group by hydrogenation to produce the corresponding aniline derivative, acylation of the aniline intermediate with 4-(carbomethoxy)benzoyl chloride, and hydrolysis of the methyl ester.