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Blair W.S.,Pfizer | Blair W.S.,Genentech | Pickford C.,Pfizer | Irving S.L.,Pfizer | And 20 more authors.
PLoS Pathogens | Year: 2010

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy. © 2010 Blair et al.


PubMed | University of British Columbia, McMaster University, Fedora Pharmaceuticals, Université de Sherbrooke and NAEJA Pharmaceutical Inc.
Type: Journal Article | Journal: ACS chemical biology | Year: 2016

Avibactam is a diazabicyclooctane -lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with -lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important -lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC 2 g/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both -lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.


Shustov G.,NAEJA Pharmaceutical Inc. | Khlebnikov V.,NAEJA Pharmaceutical Inc.
Canadian Journal of Chemistry | Year: 2011

A new method for synthesizing chiral 3,3′-bis(N,N-dialkylaminomethyl) -1,1′-bi-2-naphthols with high enantiomeric excess is described. The procedure consists of bis-lithiation of diprotected (S)-or (R)-1,1′-bis(2- naphthol) followed by treatment of the intermediate with methyleneiminium salts. Mild reaction conditions prevent racemization and provide 3,3′-bis(N,N- dialkylaminomethyl)-1,1′-bi-2-naphthols or 3-(N,N-dialkylaminomethyl)-1, 1′-bi-2-naphthols with an enantiomeric excess >99%. © 2011 Published by NRC Research Press.


Khmelnitsky Y.L.,AMRI | Mozhaev V.V.,AMRI | Cotterill I.C.,AMRI | Michels P.C.,AMRI | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2013

The structures of the two predominant metabolites (M4 and M5) of RVX-208, observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies, were determined. A panel of biocatalytic systems was tested to identify biocatalysts suitable for milligram scale production of metabolite M4 from RVX-208. Rabbit liver S9 fraction was selected as the most suitable system, primarily based on pragmatic metrics such as catalyst cost and estimated yield of M4 (∼55%). Glucuronidation of RVX-208 catalyzed by rabbit liver S9 fraction was optimized to produce M4 in amounts sufficient for structural characterization. Structural studies using LC/MS/MS analysis and 1H NMR spectroscopy showed the formation of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid. NMR results suggested that the glycosidic bond has the β-anomeric configuration. A synthetic sample of M4 confirmed the proposed structure. Metabolite M5, hypothesized to be the carboxylate of RVX-208, was prepared using human liver microsomes, purified by HPLC, and characterized by LC/MS/MS and 1H NMR. The structure was confirmed by comparison to a synthetic sample. Both samples confirmed M5 as a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid. © 2013 Elsevier Inc. All rights reserved.


Brouwer C.P.J.M.,Leiden University | Rahman M.,NAEJA Pharmaceutical Inc. | Welling M.M.,Leiden University
Peptides | Year: 2011

There is an urgent need to develop new antimicrobial drugs especially for combating the rise of infections caused by multi-resistant pathogens such as MRSA and VRSA. The problem of antibiotic resistant micro-organisms is expected to increase disproportionally and controlling of infections is becoming difficult because of the rapid spread of those micro-organisms. Primary therapy with classical antibiotics is becoming more ineffective. Combinational therapy of antibiotics with antimicrobial peptides (AMP's) has been suggested as an alternative approach to improve treatment outcome. Their unique mechanism of action and safety profile makes AMP's appealing candidates for simultaneous or sequential use in different cases of infections. In this review, for antimicrobial treatment the application of synthetic antimicrobial peptide hLF(1-11), derived from the first 11 amino acids of human lactoferrin is evaluated in both pre-clinical and clinical settings. Present information indicates that this derivate from lactoferrin is well tolerated in pre-clinical tests and clinical trials and thus hLF(1-11) is an interesting candidate for further exploration in various clinical indications of obscure infections, including meningitis. Another approach of using AMP's is their use in prevention of infections e.g. as coating for dental or bone implants or in biosensing applications or useful as infection specific radiopharmaceutical. © 2011 Elsevier Inc.


A compound of formula (I):


A compound of formula (I): wherein:


A compound of formula (I) or formula (Ia) Wherein R_(1), R_(a), R_(2), X, R_(3), Y_(1), Y_(2), A, B and C are as defined herein. Also, pharmaceutical compositions comprising such compounds and excipients, methods of treating bacterial infections comprising administering such compounds, methods for making such compounds and hydrates of such compounds.


A compound of formula (I): wherein:


New bicyclic compounds, their preparation, and their use as antibacterial agents, either alone or in combination with an antibiotic for the treatment of infections caused by -lactamase-producing pathogenic bacteria, are described.

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