Orally active water-soluble N,O-acyl transfer products of a .beta.,.gamma.-bishydroxyl amide containing renin inhibitor

Hurley, Timothy R.; Colson, Charles E.; Hicks, Gary W.; Ryan, Michael J.

doi:10.1021/jm00062a024

Cited by 35 publications

(17 citation statements)

References 1 publication

(1 reference statement)

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“…Hurley et al also reported a study on the O-N-acyl migration of renin inhibitors. 21 From these findings, a new prodrug concept based on O-N intramolecular acyl migration was established, and the sparingly water-soluble drugs with an N-acyl-2-aminoethanol structure are generally potential targets for this water-soluble prodrug strategy.…”

Section: Introductionmentioning

confidence: 99%

ON intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence‐containing bioactive peptides

et al. 2004

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N-Ointramolecular acyl migration in Ser- or Thr-containing peptides is a well-known side reaction in peptide chemistry. It results in the mutual conversion of ester and amide bonds. Our medicinal chemistry study focused on the fact that the O-acyl product can be readily converted to the original N-acyl form under neutral or slightly basic conditions in an aqueous buffer and the liberated ionized amino group enhances the water solubility of O-acyl products. Because of this, we have developed a novel class of "O-N intramolecular acyl migration"-type water-soluble prodrugs of HIV-1 protease inhibitors. These prodrugs released the parent drugs via a simple chemical mechanism with no side reaction. In this study, we applied this strategy to important cancer chemotherapeutic agents, paclitaxel and its derivatives, to develop water-soluble taxoid prodrugs, and found that these prodrugs, 2'-O-isoform of taxoids, showed promising results with higher water solubility and proper kinetics in their parent drug formation by a simple pH-dependent chemical mechanism with O-N intramolecular acyl migration. These results suggest that this strategy would be useful in toxicology and medical economics. After the successful application of O-N intramolecular acyl migration in medicinal chemistry, this concept was recently used in peptide chemistry for the synthesis of "difficult sequence-containing peptides." The strategy was based on hydrophilic O-acyl isopeptide synthesis followed by the O-N intramolecular acyl migration reaction, leading to the desired peptide. In a model study with small, difficult sequence-containing peptides, synthesized "O-acyl isopeptides" not only improved the solubility in various media and efficiently performed the high performance liquid chromatography purification, but also altered the nature of the difficult sequence during SPPS, resulting in the efficient synthesis of O-acyl isopeptides with no complications. The subsequent O-N intramolecular acyl migration of purified O-acyl isopeptides afforded the desired peptides as precipitates with high yield and purity. Further study of the synthesis of a larger difficult sequence-containing peptide, Alzheimer's disease-related peptide (A beta 1-42), surprisingly showed that only one insertion of the O-acyl group drastically improved the unfavorable nature of the difficult sequence in A beta 1-42, and achieved efficient synthesis of 26-O-acyl isoA beta 1-42 and subsequent complete conversion to A beta 1-42 via the O-N intramolecular acyl migration reaction of 26-O-acyl isoA beta 1-42. This suggests that our new method based on O-N intramolecular acyl migration is an important method for the synthesis of difficult sequence-containing bioactive peptides.

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Section: Introductionmentioning

confidence: 99%

ON intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence‐containing bioactive peptides

et al. 2004

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“…Besides being used as intermediates to achieve the synthesis of difficult peptides, depsipeptides found important application as models for the studies of folding and association processes (the so‐called switch‐ or click‐peptides)21–23 and for the development of prodrugs with enhanced water‐solubility24–26.…”

Section: Depsipeptide Strategymentioning

confidence: 99%

The depsipeptide method for solid‐phase synthesis of difficult peptides

Coin

2010

Journal of Peptide Science

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After about one century of peptide chemistry, the main limitation to the accessibility of peptides and proteins via chemosynthesis is the arising of folding and aggregation phenomena. This is true not only for sequences above a critical length but also for several biologically relevant substrates that are relatively short yet form either highly folded structures (e.g. WW domains) or fibrils and aggregates after final deprotection (beta-amyloid peptide). Such so-called difficult sequences may be more easily obtained via their corresponding depsipeptides (O-acyl isopeptides), ester isomers that are often easier to assemble and purify, and are smoothly converted to the parent amides under mild conditions. The depsipeptide method is the most recent technique to improve the outcome of difficult syntheses, applicable to sequences containing residues of serine or threonine. A brief overview is presented about chemical aspects of the method, the steps that have been undertaken for its optimization, and the evaluation of its efficiency. Further applications of analogous principles to other critical topics in peptide synthesis such as condensation of peptide segments and solid-phase synthesis of naturally occurring cyclodepsipeptides are addressed as well.

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“…The second prodrug application [72] is based on the concept of O-to N-acyl migration, a strategy pioneered previously for aspartyl protease inhibitors such as renin inhibitors [73] and HIV-1 protease inhibitors [74][75][76]. The design of these prodrugs is based on the high watersolubility of the amine 34 at acidic pH and the facile O-to N-migration that occurs at more basic pH to afford the amide alcohol 35.…”

Section: Hydroxyethylamine Isosteresmentioning

confidence: 99%

Progress in the Discovery of BACE Inhibitors

Thompson¹,

Bronson²,

Zusi³

2005

CPD

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Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of beta-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.

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Orally active water-soluble N,O-acyl transfer products of a .beta.,.gamma.-bishydroxyl amide containing renin inhibitor

Cited by 35 publications

References 1 publication

ON intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence‐containing bioactive peptides

ON intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence‐containing bioactive peptides

The depsipeptide method for solid‐phase synthesis of difficult peptides

Progress in the Discovery of BACE Inhibitors

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