Antisense Medicinal Chemistry

Cook, P. Dan

doi:10.1007/978-3-642-58785-6_2

Cited by 35 publications

(25 citation statements)

References 123 publications

(79 reference statements)

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“…In particular, 2Ј-O-(2-methoxyethyl) (2Ј-MOE) modifications have greatly increased binding affinity to the target mRNA, improved nuclease resistance (Cook, 1998), altered pharmacokinetics (Bennett et al, 2000;Geary et al, 2001a), and shown potentially improved safety profiles (Henry et al, 2001).…”

mentioning

confidence: 99%

PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-O-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES

Geary¹,

Yu²,

Watanabe³

et al. 2003

Drug Metab Dispos

159

128

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The pharmacokinetics of a 2-O-(2-methoxyethyl)-ribose modified phosphorothioate oligonucleotide, ISIS 104838 (human tumor necrosis factor-␣ antisense), have been characterized in mouse, rat, dog, monkey, and human. Plasma pharmacokinetics after i.v. administration exhibited relatively rapid distribution from plasma to tissues with a distribution half-life estimated from approximately 15 to 45 min in all species. Absorption after s.c. injection was high (80-100%), and absorption after intrajejunal administration in proprietary formulations was as high as 10% bioavailability compared with i.v. administration. Urinary excretion of the parent drug was low, with less than 1% of the administered dose excreted in urine after i.v. infusion in monkeys at clinically relevant doses (<5 mg/ kg). ISIS 104838 is highly bound to plasma proteins, likely preventing renal filtration. However, shortened oligonucleotide metabolites of ISIS 104838 lose their affinity to bind plasma proteins. Thus, excretion of radiolabel (mostly as metabolites) in urine (75%) and feces (5-10%) was nearly complete by 90 days. Elimination of ISIS 104838 from tissue was slow (multiple days) for all species, depending on the tissue or organ. The highest concentrations of ISIS 104838 in tissues were seen in kidney, liver, lymph nodes, bone marrow, and spleen. In general, concentrations of ISIS 104838 were higher in monkey tissues than in rodents at body weight-equivalent doses. Plasma pharmacokinetics scale well across species as a function of body weight alone. This favorable pharmacokinetic profile for ISIS 104838 provides guidance for clinical development and appears to support infrequent and convenient dose administration.

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mentioning

confidence: 99%

PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-O-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES

Geary¹,

Yu²,

Watanabe³

et al. 2003

Drug Metab Dispos

159

128

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“…Among the derivatives described, only phosphodiester, phosphorothioates, and boranophosphates DNAs direct RNase H mediated degradation of hybridized RNA. Encouraging results have been obtained suggesting that greater potency and a better specificity might be possible with 2′-O-alkyl RNA, phosphorothioate chimeras, anomeric DNA chimeras, or DNA boranophosphates [35, 40]. …”

Section: In Vivo Gene Imaging Agentsmentioning

confidence: 99%

Imaging oncogene expression

Mukherjee¹,

Wickstrom²,

Thakur³

2009

European Journal of Radiology

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This review briefly outlines the importance of molecular imaging, particularly imaging of endogenous gene expression for noninvasive genetic analysis of radiographic masses. The concept of antisense imaging agents and the advantages and challenges in the development of hybridization probes for in vivo imaging are described. An overview of the investigations on oncogene expression imaging is given. Finally, the need for further improvement in antisense-based imaging agents and directions to improve oncogene mRNA targeting is stated.

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“…Although the synthesis of modi®ed nucleic acids has been a subject of interest for some time (Sproat et al, 1989; see DNA synthesis), the intense focus on the medicinal chemistry of oligonucleotides dates perhaps no more than the past 10 years. Modi®cations have been made to the base, sugar and phosphate moieties of oligonucleotides (Figure 2) (for review, see Cook, 1998;Crooke, 1998;Manoharan, 1999). The subjects of medicinal chemical programs include approaches to (i) create enhanced and more selective a nities for RNA or duplex structures; (ii) the ability to cleave nucleic acid targets; (iii) enhanced nuclease stability; (iv) cellular uptake and distribution; and (v) in vivo tissue distribution, metabolism and clearance.…”

Section: Medicinal Chemistry Of Oligonucleotidesmentioning

confidence: 99%

Potential roles of antisense technology in cancer chemotherapy

Crooke

2000

Oncogene

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IntroductionProgress in sequencing the human genome has resulted in optimism that we will shortly have a much better understanding of health and disease and the factors that contribute to both at the molecular level. Armed with these insights, we will then be able to rapidly e ect dramatic improvement in the prevention and treatment of many diseases and enhance the productivity of the drug discovery and development process. For no disease is there a greater need, and therefore more hope, that genomic information will result in revolutionary advances than cancer.Nevertheless, to achieve the full bene®t of the genomic revolution, investment in technologies that can convert genomic information into therapeutic gains and enhanced drug discovery and development productivity is a must. Again, for no disease is this more apparent than cancer. Speci®cally, technologies that can take genomic information directly and rapidly and e ciently create gene-speci®c inhibitors that can be used to functionalize and validate as good drug targets various genes are required. Development technologies that can result in dramatically more speci®c drugs, classes of drugs that can be more easily used in combination and for which the failure rates in preclinical and early clinical trials are much lower also musts.Antisense technology is arguably the most advanced genomically-based drug discovery technology. It has been shown to be capable of generating very speci®c inhibitors and a signi®cant number of antisense drugs are in development as anticancer agents.In this review I will brie¯y summarize the current state of antisense technology, the pharmacodynamic, pharmacokinetic and toxicological properties of antisense drugs, and the current applications of antisense technology in cancer, including gene functionalization and therapeutic target validation.

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Antisense Medicinal Chemistry

Cited by 35 publications

References 123 publications

PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-O-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES

PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-O-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES

Imaging oncogene expression

Potential roles of antisense technology in cancer chemotherapy

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