- Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors
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A compound having the formula: wherein all variables are as defined in the specification, for use as a neuramninidase inhibitor.
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- Design of benzoic acid inhibitors of influenza neuraminidase containing a cyclic substitution for the N-acetyl grouping
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A 2-pyrrolidinone ring containing a single hydroxymethyl side chain effectively replaces the N-acetylamino group of 4-(N-acetylamino)-3- guanidinobenzoic acid, a low micromolar inhibitor of influenza neuraminidase. This novel structural template affords new opportunities to evolve more potent benzoic acid inhibitors.
- Brouillette, Wayne J.,Atigadda, Venkatram R.,Ming, Luo,Air, Gillian M.,Babu, Yarlagadda S.,Bantia, Shanta
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p. 1901 - 1906
(2007/10/03)
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- Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent
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On the basis of the lead compound 4-(N-acetylamino)-3-guanidinobenzoic acid (BANA 113), which inhibits influenza A sialidase with a K(i) of 2.5 μM, several novel aromatic inhibitors of influenza sialidases were designed. In this study the N-acetyl group of BANA 113 was replaced with a 2- pyrrolidinone ring, which was designed in part to offer opportunities for introduction of spatially directed side chains that could potentially interact with the 4-, 5-, and/or 6-subsites of sialidase. While the parent structure 1-(4-carboxy-2-guanidinophenyl)pyrrolidin-2-one (8) was only a modest inhibitor of sialidase, the introduction of a hydroxymethyl or bis(hydroxymethyl) substituent at the C5' position of the 2-pyrrolidinone ring resulted in inhibitors (9 and 12, respectively) with low micromolar activity. Crystal structures of these inhibitors in complex with sialidase demonstrated that the substituents at the 5'-position of the 2-pyrrolidinone ring interact in the 4- and/or 5-subsites of the enzyme. Replacement of the guanidine in 12 with a hydrophobic 3-pentylamino group resulted in a large enhancement in binding to produce an inhibitor (14) with an IC50 of about 50 nM against influenza A sialidase, although the inhibition of influenza B sialidase was 2000-fold less. This represents the first reported example of a simple, achiral benzoic acid with potent (low nanomolar) activity as an inhibitor of influenza sialidase.
- Atigadda, Venkatram R.,Brouillette, Wayne J.,Duarte, Franco,Ali, Shoukath M.,Babu, Yarlagadda S.,Bantia, Shanta,Chand, Pooran,Chu, Naiming,Montgomery, John A.,Walsh, David A.,Sudbeck, Elise A.,Finley, James,Luo, Ming,Air, Gillian M.,Laver, Graeme W.
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p. 2332 - 2343
(2007/10/03)
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