Structure-Activity Relationship of Orally Potent Tripeptide-Based HIV Protease Inhibitors Containing Hydroxymethylcarbonyl Isostere.

Mimoto, Tsutomu; Hattori, Naoko; Takaku, Haruo; Kisanuki, Sumitsugu; Fukazawa, Tominaga; Terashima, Keisuke; Kato, Ryohei; Nojima, Satoshi; Misawa, S.; Ueno, Takamasa; Imai, Junya; Enomoto, Hiroshi; Tanaka, Shigeki; Sakikawa, Hiroshi; Shintani, Makoto; Hayashi, Hideya; Kiso, Yoshiaki

doi:10.1248/cpb.48.1310

Cited by 46 publications

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“…6 -11 These inhibitors contain an ␣-hydroxy-␤-amino acid residue, allophenylnorstatine [Apns, (2S, 3S)-3-amino-2-hydroxy-4-phenylbutanoic acid], which has a hydroxymethylcarbonyl (HMC) isostere derived from a natural scissile amino acid sequence "Phe-Pro." [12][13][14][15][16][17][18][19][20] As depicted in Figures 1B and C, these "O-N intramolecular acyl migration"-type water-soluble prodrugs of HIV-1 protease inhibitors, which are O-acyl isoforms of the parent drugs, increase water solubility and are easily converted to the corresponding N-acyl forms, i.e., parent drugs via O-N intramolecular acyl migration. This migration can be precisely controlled by pH and is completed in a short time with no side reactions under physiological conditions (pH 7.4).…”

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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“…4. Although KNI-272 showed good oral bioavailability in a human clinical trial, the plasma half-life was very short (t 1/2b = 23 min, intravenous), which suggested that the inhibitor must be further optimized for a more desirable pharmacokinetic profile [24].…”

Section: Hiv Protease Inhibitorsmentioning

confidence: 99%

“…This observation suggested that the P2-P29 residues form the pharmacophore of the inhibitor. As a result, we opted to discard the P2-cap moiety and altered the design of the P2 residue to a P1-cap moiety [24]. According to an extensive literature search, a variety of ligands optimized for binding to the S2 subsite of HIV protease had been reported for hydroxyethylamine inhibitors, namely 2,6-dimethylphenoxyacetyl and 3-hydroxy-2-methylbenzoyl groups.…”

Section: Hiv Protease Inhibitorsmentioning

confidence: 99%

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

Nguyen

Hamada

Kimura

et al. 2008

Archiv der Pharmazie

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In this retrospective, personal review covering our research from the late 1980s until 2007, we outline nearly two-decade worth of our own work on several aspartic protease inhibitors including those affecting renin, HIV-1 protease, plasmepsins, b-secretase, and HTLV-I protease and we report on aspartic protease inhibitors as potential drugs to treat hypertension, AIDS, malaria, Alzheimer's disease and adult T-cell leukemia, HTLV-I associated myelopathy / tropical spastic paraparesis, and various, respectively, associated diseases. Herein, we describe our methods for rational substrate-based drug design of peptidomimetics that potently inhibit the activity of renin, HIV-1 protease, plasmepsins, b-secretase, and HTLV-I protease accordingly, using an appropriately selected inhibitory residue that contained a hydroxymethylcarbonyl isostere. Although this non-hydrolyzable isostere mimics the transition state that is formed during protein cleavage of a substrate, the isostere-containing inhibitor is not cleaved. We highlight our optimization studies in which we used various techniques and tools such as truncation studies, natural and non-natural amino acid substitution studies, various moieties to promote chemical and pharmacological stability, X-ray crystallography, computer-assisted docking and dynamic simulations, quantitative structure-activity relationship studies, and various other methods that this review can barely mention.

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“…Das Norstatinisoster 3 (Schema 1) wurde als eine erste Zielstruktur unserer Studien ausgewählt, da es eine Klasse potenter Inhibitoren der Metallo-und Aspartylproteasen repräsentiert. [11,12] Das Polystyrolgebundene Triphenylphosphanderivat 4 (Schema 2, 1.2 mmol g À1 ) ist ein klassisches polymeres Reagens, [13,14] das routinemäßig in polymerunterstützten Halogenierungen, Mitsunobu-und Wittig-Reaktionen Anwendung findet. [14,15] Unserer Kenntnis nach ist dies der erste Bericht über die …”

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Ein Phosphoran als polymergebundenes Acylanionenäquivalent: Linkerreagentien für schonende und vielseitige C‐C‐Kupplungen

Weik

Rademann

2003

Angewandte Chemie

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Structure-Activity Relationship of Orally Potent Tripeptide-Based HIV Protease Inhibitors Containing Hydroxymethylcarbonyl Isostere.

Cited by 46 publications

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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

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

Ein Phosphoran als polymergebundenes Acylanionenäquivalent: Linkerreagentien für schonende und vielseitige C‐C‐Kupplungen

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