Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

Abstract

GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (C maxs; C max<0.06 μg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high C maxs of GS 4071 (Cmax = 0.47 μg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

Development of Influenza Virus Sialidase Inhibitors

“…The corresponding guanidino derivative 25 showed only relatively minor increase in inhibitory potency (IC 50 0.5 nM) [152]. Both compounds also inhibited replication of influenza viruses in cell culture, with the guanidino derivative 10-fold more effective than 6 [156]. Amino derivative 6 showed no inhibition of the four human sialidases at tested concentrations in the mM range (IC 50 values > 6 mM) [124].…”

“…Despite the significantly increased lipophilicity of guanidino derivative 25 and in particular the amino derivative 6 compared to zanamivir 5, both com pounds 25 and 6 showed poor oral bioavailability (4% in a rat model, equiv alent to zanamivir) [156]. While formation of the ethyl ester at the carboxylic acid failed to improve the bioavailability of the guanidino derivative 25, it increased oral bioavailability of 6 significantly (to 35% in the rat) [156].…”

“…While formation of the ethyl ester at the carboxylic acid failed to improve the bioavailability of the guanidino derivative 25, it increased oral bioavailability of 6 significantly (to 35% in the rat) [156]. The ester of 7 is cleaved by endogenous esterases, releasing the active metabolite 6, which is distributed throughout the body including to the respiratory tract and lungs [157].…”

Interplay between influenza A virus and host factors: targets for antiviral intervention

“…Currently, there are two classes of clinically approved antiinfluenza drugs: adamantanes (amantadine and rimantadine), which target the ion channel activity of the M2 protein, and neuraminidase inhibitors (oseltamivir and zanamivir) [154][155][156][157]. The major issue with these drugs is the rapid evolution of resistance in influenza A viruses due to the notoriously low fidelity of the viral polymerase.…”

Pharmacokinetics and bioavailability of oral cephalosporins, KR-984055 and its prodrugs, KR-999001 and KR-999002, in the rat

“…A suitable intervals, 300 j..ll aliquots were withdrawn and deproteinated immediately with equal volume of 6% trichloroacetic acid (TCA) (Li et al, 1998). After mixing and centrifugation, 50 j..ll of the supernatant was injected into chromatograph.…”