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Linzagolix choline (KLH-2109 choline) is a non-peptide gonadotropin-releasing hormone (GnRH) antagonist with oral activity. Linzagolix choline inhibits the release of endogenous gonadotropins such as luteinizing hormone LH and follicle-stimulating hormone FSH by binding to the GnRH receptor within the pituitary gland. This inhibition results in a reduction in the production of sex hormones such as estrogen and progesterone, which in turn affects the course of sex hormone-dependent diseases. Linzagolix choline can be used in the study of sex hormone-dependent diseases such as endometriosis and uterine fibroids[1]. | [Indications]
Linzagolix Choline is an oral small molecule drug approved by the USFDA, Europe and Japan for the treatment of moderate to severe symptomatic uterine fibroids in adult women, a sex hormone-dependent pelvic tumor that affects up to 50-60% of women of childbearing age. | [Mechanism of action]
Linzagolix is a gonadotropin-releasing hormone (GnRH) antagonist that acts on the GnRH receptors of the pituitary gland, modulating the hypothalamic-pituitary-gonadal axis, thereby reducing estrogen and progesterone levels. By reducing the levels of these steroids, Linzagolix Choline is able to reduce menstrual bleeding, relieve pain and pelvic discomfort and other symptoms associated with uterine fibroids. | [Side effects]
Side effects of Linzagolix Choline may include hot flashes, headache, nausea, and diarrhea. | [Synthesis]
The synthesis of Linzagolix Choline is accomplished via an efficient two-component polymerization, as shown in Figures 1 and 2. The synthesis of the first component, intermediate 35.6, begins with the reaction of dimethyl maleate 35.1 and methyl thioacetate 35.2 under alkaline conditions (Figure 1). After treatment under mild acidic conditions, a crystalline solid cyclic thiol compound 35.3 is obtained. This cyclic thiol is then converted to the corresponding thiophene by aromatization. The ketone 35.3 is converted to the corresponding oxime by treatment with hydroxylamine hydrochloride in warm pyridine, and the resulting oxime is then treated under strongly acidic conditions to afford the aminothiophene 35.5, a sequence known as the Semmler–Wolff aromatization reaction. Finally, 35.5 is reacted with phenyl chloroformate to afford the carbamate intermediate 35.6 in 92% yield.
The synthesis of the second component, intermediate 35.11, begins with sodium borohydride reduction of the aldehyde 35.7 to the corresponding alcohol, which is subsequently chlorinated using concentrated hydrochloric acid (Figure 2). The bromide is then generated in situ and tetrabutylammonium bromide is added to achieve this. Under alkaline conditions, the ether is formed by adding phenol 35.8 to obtain ether 35.9, and the total yield of the three-step reaction is 89%. Conventional nitration conditions are then used to obtain compound 39.10. Raney nickel reduction is used to obtain the corresponding amine, thereby synthesizing the key aniline intermediate 35.11. At this point, the two higher intermediates 35.6 and 35.11 are condensed under alkaline conditions to produce a high-yield urea 35.12. 35.12 is exposed to the carboxyl group under the action of lithium hydroxide, and the intramolecular cyclization reaction is promoted by acidic conditions. It is then treated with choline carbonate to precipitate Linzagolix Choline, which is finally isolated as a choline salt.
 | [References]
[1] Kobayashi K, et al. Non-clinical studies indicating lack of interactions between iron/calcium ions and linzagolix, an orally available GnRH antagonist[J]. Xenobiotica, 2022, 52(5): 488-497. DOI:10.1080/00498254.2022.2109076 |
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