Bilastine

Bilastine, a potent and selective histamine H1 receptor antagonist, was approved in Europe in 2010 for the treatment of allergic rhinoconjunctivitis (AR) and urticaria (hives or skin rash). The original synthesis of bilastine involves alkylation of 2-piperidinyl-1H-benzimidazole with a phenethyltosylate, the para position of which is substituted with a dimethyloxazoline moiety serving as a masked carboxylic acid group. Alkylation of the benzimidazole nitrogen with 2-chloroethyl ethyl ether followed by unmasking of the oxazoline moiety with sulfuric acid provided bilastine.
In two major clinical trials, bilastine was effective at relieving allergic rhinitis as assessed by measuring the severity of nasal (obstruction, rhinorrhea, itching, sneezing) and nonnasal (ocular itching, tearing, ocular redness, itching of ears, and/or palate) symptoms.

Bilastine is a histamine H₁ receptor antagonist (IC₅₀ = 180 nM). It is selective for the histamine H₁ receptor in a panel of 30 receptors in vitro at 100 μM. Bilastine prevents microvascular extravasation (ED₅₀ = 185 μg/kg, i.v.), bronchospasm (ED₅₀ = 4.6 μg/kg, i.v.), and systemic anaphylaxis (ED₅₀ = 0.2 μg/kg, p.o.) induced by subcutaneous histamine in guinea pigs. It prevents anaphylaxis induced by subcutaneous administration of ovalbumin or dinitrophenylated human albumin (DNP) in sensitized rats when administered at doses of 7.6 and 6.0 mg/kg, respectively. Formulations containing bilastine have been used in the treatment of urticaria and allergic rhinitis.

FAES FARMA, S.A. (Spain)

Labelled Bilastine. It is a novel, nonsedating H1-antihistamine developed for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria.

Bilastine is a novel, nonsedating H1-antihistamine developed for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria.

ChEBI: Bilastine is a member of benzimidazoles.

Bilaxten

Bilastine is a selective histamine H1 antagonist approved for the treatment of allergic rhinoconjunctivitis and urticaria (hives). This drug, which has proven to be well tolerated in toxicology profiling, 46 was discovered by the Spainsh firm FAES Farma and was approved by the European Union in 2010.

In 2011, Collier and co-workers published a communication describing both the original synthesis of bilastine and an improved route which was amenable to gram-scale production. Collier?ˉs second generation route, shown below, relies upon a convergent approach involving the union of piperidinyl benzimidazole 49 with fully functionalized phenethyl electrophile 48.Coupling the commercially available bromophenyl acetate 44 with cyclic trioxatriborinane 45 under conventional Suzuki conditions furnished styrene 46 in good yield. Alternatively, this vinylation reaction was also performed under Stille conditions with tributyl vinyl stannane in 83% yield. Hydroboration¨Coxidation of 46 delivered phenethyl alcohol 47 which was then immediately mesylated under basic conditions in toluene to produce adduct 48. This sulfonate was then reacted with piperidine 49 (whose preparation is described in Scheme 7) followed by saponification of the resulting ester 50 to arrive at bilastene (VI) in 26% overall yield from 44.



For the preparation of bilastine piperidine 49, commercially available piperidine 51 was first protected as the Boc-carbamate 52 prior to alkylation of the benzimidazole nitrogen atom with 1-chloro-2-ethoxyethane 53, providing compound 54. The Boc group of 54 was removed under acidic conditions to give fragment 49. This sequence produced the desired piperidine component in 86% overall yield from 51.

Potentially hazardous interactions with other drugs
Antivirals: concentration possibly increased by ritonavir.
Grapefruit juice: concentration of bilastine reduced.

Not significantly metabolised. Almost 95% of the administered dose was recovered in urine (28.3%) and faeces (66.5%) as unchanged bilastine