Cary, NC, United States


Cary, NC, United States
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Ramamurty C.V.S.,Natural Products and Glycotechnology Research Institute Inc. | Ganney P.,Natural Products and Glycotechnology Research Institute Inc. | Rao C.S.,CiVentiCHEM | Fraser-Reid B.,Natural Products and Glycotechnology Research Institute Inc.
Journal of Organic Chemistry | Year: 2011

The 3,5-di-O-benzoyl n-pentenyl orthoesters of the four pentofuranoses have been prepared. The first key intermediate in each case is the methyl pentofuranoside(s), and a user-friendly procedure for the preparation of each, based on the Callam-Lowary precedent, is described, whereby formation of the crucial α/β anomeric mixture is optimized. The mixture is used directly to prepare the corresponding perbenzoylated pentofuranosyl bromide(s) and then the title compounds. © 2011 American Chemical Society.

Khmelnitsky Y.L.,Circle Inc. | Michels P.C.,Circle Inc. | Cotterill I.C.,Circle Inc. | Eissenstat M.,Sequoia Pharmaceuticals Inc. | And 8 more authors.
Organic Process Research and Development | Year: 2011

A simple and efficient process has been developed to effect the kinetic resolution of the racemic alcohol 2 using immobilized lipase to afford the desired optically pure (R)-bis-tetrahydrofuran (bis-THF) alcohol 3, to facilitate the rapid progression of a clinical candidate. Rapid optimization and development of reproducible and scalable processes are essential to meet aggressive timeframes for preclinical, safety, and early clinical drug development. Process parameters were initially scoped and optimized using a combination of a rational bioprocess screening design and parallel microscale empirical studies, specifically accounting for scale-up and downstream processing considerations. The choices of reaction solvent, acyl donor, and immobilized biocatalyst proved to be critical factors in the design of a conveniently scalable and enantioselective enzymatic resolution process. The improved process was initially validated on 3-g and then 90-g scale in simple impeller-stirred reactors, exhibiting excellent reproducibility. This methodology was successfully implemented on a multikilogram scale to give the target alcohol 3 with >99% ee. © 2010 American Chemical Society.

McGuigan C.,University of Cardiff | Madela K.,University of Cardiff | Aljarah M.,University of Cardiff | Gilles A.,University of Cardiff | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

We have previously reported the power of combining a 5′- phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2′-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism. © 2011 Elsevier Ltd. All rights reserved.

McGuigan C.,University of Cardiff | Madela K.,University of Cardiff | Aljarah M.,University of Cardiff | Bourdin C.,University of Cardiff | And 20 more authors.
Journal of Medicinal Chemistry | Year: 2011

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2′-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both D and L, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases. © 2011 American Chemical Society.

Bourdin C.,University of Cardiff | McGuigan C.,University of Cardiff | Brancale A.,University of Cardiff | Chamberlain S.,Inhibitex | And 17 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

7-Deazapurines are known to possess broad antiviral activity, however the 2′-C-methylguanosine analogue displays poor cell permeation and limited phosphorylation, thus is not an efficient inhibitor of hepatitis C virus (HCV) replication. We previously reported the 6-O-methyl entity as a prodrug moiety to increase liphophilicity of guanine nucleosides and the ProTide approach applied to 2′-C-methyl-6-O-methylguanosine has lead to potent HCV inhibitors now in clinical trials. In this Letter, we report the synthesis and biological evaluation of 2′-C-methyl-6-O-methyl-7-deaza guanosine and ProTide derivatives. In contrast to prior studies, removal of the N-7 of the nucleobase entirely negates anti-HCV activity compared to the 2′-C-methyl-6-O- methylguanosine analogues. To understand better this significant loss of activity, enzymatic assays and molecular modeling were carried out and suggested 2′-C-methyl-6-O-methyl-7-deaza guanosine and related ProTides do not act as efficient prodrugs of the free nucleotide, in marked contrast to the case of the parent guanine analogue. © 2013 Elsevier Ltd. All rights reserved.

ortho-Lithiation of N-Boc-3-bromopyrroles (7b, 7d) with LDA in THF at -75 °C, followed by reactions with ethyl formate gave exclusive C2-formylpyrroles (9b, 9c, 9d, 9e) in good yields. This methodology was applied to the synthesis of 3-(2-formyl-4-methyl-1-H-pyrrol-3-yl)propanoic acid (4a), a penultimate precursor to SU5402. The process for making 4a has also been optimized which involves a non-chromatography eight-step synthesis with an overall 18% yield. © 2015 Elsevier Ltd.

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