david butler - Academia.edu (original) (raw)

Papers by david butler

Research paper thumbnail of Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides

Nature biotechnology, Jan 21, 2017

Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeri... more Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3'-SpSpRp, that promotes target RNA ...

Research paper thumbnail of A Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric Synthesis

Organic Letters, 2006

Oxazole derivatives R 0220 A Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric... more Oxazole derivatives R 0220 A Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric Synthesis.-A novel chiral catalyst is prepared and found to promote effectively the Steglich rearrangement of enol carbamates. Azlactones are formed in high yields and enantioselectivities.-(NGUYEN,

Research paper thumbnail of 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) Analogues:  A Promising Class of Monoamine Uptake Inhibitors

Journal of Medicinal Chemistry, 2006

Dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian syste... more Dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research since modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT 1A , 5HT 1B , 5HT 1C , D 1 , D 2 , or D 3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4dichlorophenyl)-(4u) and the 1-naphthyl-(4t) 2-pyrrolidin-1-yl-pentan-1-one analogs.

Research paper thumbnail of Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery

Journal of Controlled Release, 2010

Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to e... more Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2′-3′-cyclic nucleotide 3′phosphodiesterase) in oligodendrocytes. Cholesterol-conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo.

Research paper thumbnail of Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides

Nature biotechnology, Jan 21, 2017

Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeri... more Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3'-SpSpRp, that promotes target RNA ...

Research paper thumbnail of A Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric Synthesis

Organic Letters, 2006

Oxazole derivatives R 0220 A Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric... more Oxazole derivatives R 0220 A Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric Synthesis.-A novel chiral catalyst is prepared and found to promote effectively the Steglich rearrangement of enol carbamates. Azlactones are formed in high yields and enantioselectivities.-(NGUYEN,

Research paper thumbnail of 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) Analogues:  A Promising Class of Monoamine Uptake Inhibitors

Journal of Medicinal Chemistry, 2006

Dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian syste... more Dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research since modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT 1A , 5HT 1B , 5HT 1C , D 1 , D 2 , or D 3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4dichlorophenyl)-(4u) and the 1-naphthyl-(4t) 2-pyrrolidin-1-yl-pentan-1-one analogs.

Research paper thumbnail of Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery

Journal of Controlled Release, 2010

Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to e... more Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2′-3′-cyclic nucleotide 3′phosphodiesterase) in oligodendrocytes. Cholesterol-conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo.