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Your search keyword '"Beno, Brett R."' showing total 3 results
Start Over Author "Beno, Brett R." Topic amides
3 results on '"Beno, Brett R."'

1. Synthesis and SAR studies of novel heteroaryl fused tetracyclic indole-diamide compounds: potent allosteric inhibitors of the hepatitis C virus NS5B polymerase.

Author

Ding M, He F, Hudyma TW, Zheng X, Poss MA, Kadow JF, Beno BR, Rigat KL, Wang YK, Fridell RA, Lemm JA, Qiu D, Liu M, Voss S, Pelosi LA, Roberts SB, Gao M, Knipe J, and Gentles RG

Subjects
Allosteric Regulation, Amides pharmacology, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Heterocyclic Compounds pharmacology, Humans, Indoles chemistry, Indoles pharmacology, Inhibitory Concentration 50, Structure-Activity Relationship, Amides chemistry, Hepacivirus drug effects, Heterocyclic Compounds chemical synthesis, Heterocyclic Compounds chemistry, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

Presented here are initial structure-activity relationship (SAR) studies on a series of novel heteroaryl fused tetracyclic indole-based inhibitors of the hepatitis C viral polymerase, NS5B. The introduction of alternative heterocyclic moieties into the indolo-fused inhibitor class significantly expands the reported SAR and resulted in the identification of pyridino analogs, typified by compounds 44 and 45 that displayed excellent potency against the NS5B polymerase of both HCV 1a and HCV 1b genotypes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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2. SAR studies on a series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides: potent inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus.

Author

Gentles RG, Ding M, Zheng X, Chupak L, Poss MA, Beno BR, Pelosi L, Liu M, Lemm J, Wang YK, Roberts S, Gao M, and Kadow J

Subjects
Amides chemical synthesis, Amides chemistry, Catalytic Domain, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Humans, Inhibitory Concentration 50, Molecular Structure, Piperazine, Piperazines chemical synthesis, Piperazines chemistry, Piperazines pharmacology, Stereoisomerism, Structure-Activity Relationship, Amides pharmacology, Enzyme Inhibitors pharmacology, Hepacivirus enzymology, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

Described herein is the initial optimization of (+/-) N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide (1), a hit discovered in a high throughput screen run against the NS5B polymerase enzyme of the hepatitis C virus. This effort resulted in the identification of (S)-N-sec-butyl-6-((R)-3-(4-(trifluoromethoxy)benzylcarbamoyl)-4-(4-(trifluoromethoxy)phenylsulfonyl)piperazin-1-yl)pyridazine-3-carboxamide (2), that displayed potent replicon activities against HCV genotypes 1b and 1a (EC(50) 1b/1a=7/89 nM)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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3. Investigation of the mode of binding of a novel series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides to the hepatitis C virus polymerase.

Author

Gentles RG, Sheriff S, Beno BR, Wan C, Kish K, Ding M, Zheng X, Chupak L, Poss MA, Witmer MR, Morin P, Wang YK, Rigat K, Lemm J, Voss S, Liu M, Pelosi L, Roberts SB, Gao M, and Kadow JF

Subjects
Amides chemical synthesis, Amides pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Binding Sites, Computer Simulation, Crystallography, X-Ray, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Hepacivirus drug effects, Viral Nonstructural Proteins metabolism, Amides chemistry, Antiviral Agents chemistry, Enzyme Inhibitors chemistry, Hepacivirus enzymology, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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