Peramivir

Description

Peramivir is a neuraminidase (NA) inhibitor that was approved in Japan in 2010 for treatment of patients with influenza. It is the only NA inhibitor available for IV use and is the first of two NA inhibitors approved in 2010, the second being the inhaled drug laninamivir octanoate . Peramivir is the only NA inhibitor approved for IV use,which gives it a unique place in influenza treatment for seriously ill patients. Peramivir was discovered using structure-based drug design and is synthesized in six steps from Boc-protected methyl (1S,4R)-4-amino-cyclopent-2-enecarboxylate, which is prepared from 2-azabicyclo[2.2.1]hept-5-en-3-one. Cycloaddition of the cyclopentene olefin with a nitrile oxide provided an intermediate fused cyclopentane-dihydroisoxazole. Hydrogenolysis and acetylation set up a fully functionalized cyclopentane with all four stereocenters established. Deprotection of the amine and acid groups was followed by installation of the guanidine moiety to provide peramivir. Like zanamivir and oseltamivir, peramivir is a potent inhibitor of influenza virus A and B NA [strain A(H1N1) IC₅₀= 0.34 nM; strain A(H3N2) IC₅₀= 0.60 nM; strain B IC₅₀= 1.36 nM]. However, peramivir is less potent against oseltamivirresistant viruses that have the H275Y NA mutation. These viruses remain sensitive to zanamivir. Peramivir is active against influenza A and B viruses and has a lowenzymatic off-rate, suggesting that it could inhibitNAactivity for a prolonged period and allow lower frequency of dosing. Peramivir has proven efficacious in preclinical animal models of influenza infection.

Description

Peramivir is an inhibitor of influenza neuraminidase (IC₅₀s = 0.09 and 11 nM for influenza A and B neuraminidases, respectively). It is selective for influenza neuraminidase over bacterial, mammalian, and other viral neuraminidases (IC₅₀s = >300 μM). Peramivir inhibits neuraminidase activity in H1N1, H2N2, H3N2, and H6N2 influenza strains (IC₅₀s = 0.09-1.1 nM) and reduces lysis of MDCK cells infected with influenza (EC₅₀s = <0.01-21 nM). Pretreatment with peramivir (10-100 mg/kg) protects mice against lethal influenza infections. It also increases survival in ferrets infected intranasally with avian influenza type A H5N1 when injected intramuscularly after infection. Formulations containing peramivir have been used to treat influenza.

Chemical Properties

White to Off-White Solid

Originator

BioCryst Pharmaceuticals Inc. (United States)

Uses

A new antiviral agent for influenza treatment; it can be used as neuraminidase inhibitor for treating human and avian influenza.

Uses

Peramivir is a new antiviral agent for influenza treatment; it can be used as neuraminidase inhibitor for treating human and avian influenza

Definition

Peramivir is a member of the class of guanidines that is used (as its trihydrate) for the treatment of acute uncomplicated influenza in patients 18 years and older who have been symptomatic for no more than two days.

brand name

Rapiacta, PeramiFlu

Synthesis

Several syntheses of this drug have been reported and the improved route disclosed in a recent patent is described in the scheme. Ring opening of commercially available (?à)-2- azabicyclo[2.2.1]hept-5-en-3-one (117) with methanolic HCl followed by classical resolution with Ltartaric acid gave the (1S,4R)-methyl ester 118 in 85% yield. Protection of 118 with Boc anhydride and TEA in CH2Cl2 afforded carbamate 119 in 90% yield. Alkene 119 was then subject to nitrone dipolar cycloaddition conditions involving 2-ethyl-N-hydroxybutanimidoyl chloride 120 and triethylamine, followed by the basic workup and then treatment with methanolic HCl, ultimately resulting in dihydroisoxazole 121. Interestingly, the nitrone generated from 120 approached alkene 119 from the less hindered face and proceeded with remarkable regioselectivity to provide azacycle 121 in 76% yield for the three step sequence. Treatment of 121 with 1.5 eq. lithium aluminum hydride resulted in rupture of the N-O bond within this system, which afforded the amino alcohol 122 in 81% yield. It should be noted that neither the Boc group or the methyl ester were reduced under these reaction conditions. Then, a one-pot three step sequence involving acetylation of the amino group, removal of the Boc group, and hydrolysis of the carboxylic ester followed by guanylation with pyrazolecarboxamidine hydrochloride (123) provided peramivir (X) in 82% yield over the final four steps.