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Berotralstat hydrochloride is an oral plasma kallikrein inhibitor being developed by BioCryst Pharmaceuticals for the treatment of hereditary angioedema (HAE).

Berotralstat dihydrochloride is a low toxicity, effective, highly specific, second-generation, synthetic and orally active plasma kallikrein inhibitor used for the research of hereditary angioedema (HAE) attacks. Berotralstat dihydrochloride works by blocking the enzymatic activity of plasma kallikrein in releasing bradykinin, the major biologic peptide that promotes swelling and pain associated with attacks of HAE[1][2].

Berotralstat hydrochloride inhibits plasma kallikrein and reduces the production of bradykinin, thereby alleviating the symptoms of HAE patients.

Dibenzylamine 125 is treated with a base in preparation for a reductive amination reaction. Cyclopropylcarboxaldehyde is used for a reductive amination reaction to generate the corresponding amine. The above amine is reacted with oxalic acid in isopropanol to obtain cyclopropylamine 126 as an oxalate. Oxalate 126 is hydrolyzed in the presence of a base. The product of the hydrolysis is reacted with acid 120 under amide coupling conditions to generate the molecular nucleus of berotralstat as a free base 127. Finally, the free base 127 is subjected to an acid-base treatment. The treated product is subjected to hydrochloric acid in methanol to obtain berotralstat hydrochloride.

[1] Zuraw B, et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial [published online ahead of print, 2020 Oct 21]. J Allergy Clin Immunol. 2020;S0091-6749(20)31484-6. DOI:10.1016/j.jaci.2020.10.015
[2] Manning ME, et al. Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies. Allergy Asthma Proc. 2021;42(4):274-282. DOI:10.2500/aap.2021.42.210034