tetano
Editor, Senior Moderator
J Pharm Sci. 2015 Jun 2. doi: 10.1002/jps.24508. [Epub ahead of print]
[h=1]Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.[/h] Schade D[SUP]1[/SUP], Kotthaus J[SUP]1[/SUP], Riebling L[SUP]1[/SUP], Kotthaus J[SUP]1[/SUP], M?ller-Fielitz H[SUP]2[/SUP], Raasch W[SUP]2[/SUP], Hoffmann A[SUP]3[/SUP], Schmidtke M[SUP]3[/SUP], Clement B[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic. The carboxylic acid and glycerol side chain were also masked with different ester groups. The bioisosteric amidine 5 turned out to be potently active against a panel of H1N1 (IC[SUB]50[/SUB] = 2-10 nM) and H3N2 (IC[SUB]50[/SUB] = 5-10 nM) influenza A viruses (NA inhibition assay). In vitro PK studies showed that all prodrugs were highly soluble, exhibited low protein binding, and were bioactivated by N-reduction to the respective guanidines and amidines. The most promising prodrug candidates, amidoxime ester 7 and N-hydroxyguanidine ester 8, were subjected to in vivo bioavailability studies. Unfortunately, both prodrugs were not orally bioavailable to a convincing degree (F ≤ 3.7%, rats). This finding questions the general feasibility of improving the oral bioavailability of 1 by lipophilicity-increasing prodrug strategies, and suggests that intrinsic structural features represent key hurdles. ? 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
? 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
[h=4]KEYWORDS:[/h] bioavailability; drug-like properties; guanidine bioisoster; amidine; influenza A; neuraminidase inhibitor; pharmacokinetics; prodrug; synthesis
PMID: 26037932 [PubMed - as supplied by publisher]
[h=1]Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.[/h] Schade D[SUP]1[/SUP], Kotthaus J[SUP]1[/SUP], Riebling L[SUP]1[/SUP], Kotthaus J[SUP]1[/SUP], M?ller-Fielitz H[SUP]2[/SUP], Raasch W[SUP]2[/SUP], Hoffmann A[SUP]3[/SUP], Schmidtke M[SUP]3[/SUP], Clement B[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic. The carboxylic acid and glycerol side chain were also masked with different ester groups. The bioisosteric amidine 5 turned out to be potently active against a panel of H1N1 (IC[SUB]50[/SUB] = 2-10 nM) and H3N2 (IC[SUB]50[/SUB] = 5-10 nM) influenza A viruses (NA inhibition assay). In vitro PK studies showed that all prodrugs were highly soluble, exhibited low protein binding, and were bioactivated by N-reduction to the respective guanidines and amidines. The most promising prodrug candidates, amidoxime ester 7 and N-hydroxyguanidine ester 8, were subjected to in vivo bioavailability studies. Unfortunately, both prodrugs were not orally bioavailable to a convincing degree (F ≤ 3.7%, rats). This finding questions the general feasibility of improving the oral bioavailability of 1 by lipophilicity-increasing prodrug strategies, and suggests that intrinsic structural features represent key hurdles. ? 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
? 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
[h=4]KEYWORDS:[/h] bioavailability; drug-like properties; guanidine bioisoster; amidine; influenza A; neuraminidase inhibitor; pharmacokinetics; prodrug; synthesis
PMID: 26037932 [PubMed - as supplied by publisher]