Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (... more Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and t...
The S-benzyl thioester and methyl ester derivatives of a representative 4-pyridinone-based carbox... more The S-benzyl thioester and methyl ester derivatives of a representative 4-pyridinone-based carboxylic acid were sufficiently activated to react efficiently in amide coupling reactions with the amide anion generated in situ from the N-trimethylsilyl derivative of different weakly nucleophilic heteroarylamines. In acetonitrile as solvent, the precipitated diheteroarylamide products were isolated in pure form by vacuum filtration. This simple amide bond forming protocol can be readily adapted to the parallel synthesis of compound libraries.
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying st... more We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replic...
The present invention relates to novel compounds selected from 2-aminoaryloxazoles of formula I t... more The present invention relates to novel compounds selected from 2-aminoaryloxazoles of formula I that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective c-kit, bcr-abl, FGFR3 and/or Flt-3 inhibitors.
Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (... more Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and t...
The S-benzyl thioester and methyl ester derivatives of a representative 4-pyridinone-based carbox... more The S-benzyl thioester and methyl ester derivatives of a representative 4-pyridinone-based carboxylic acid were sufficiently activated to react efficiently in amide coupling reactions with the amide anion generated in situ from the N-trimethylsilyl derivative of different weakly nucleophilic heteroarylamines. In acetonitrile as solvent, the precipitated diheteroarylamide products were isolated in pure form by vacuum filtration. This simple amide bond forming protocol can be readily adapted to the parallel synthesis of compound libraries.
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying st... more We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replic...
The present invention relates to novel compounds selected from 2-aminoaryloxazoles of formula I t... more The present invention relates to novel compounds selected from 2-aminoaryloxazoles of formula I that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective c-kit, bcr-abl, FGFR3 and/or Flt-3 inhibitors.
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Papers by David Grierson