SDZ CO 611: a highly potent glycated analog of somatostatin with improved oral activity

Albert, Rainer; Marbach, Peter; Bauer, W.; Briner, U.; Fricker, Gert; Berthou, Christian; Pless, J.

doi:10.1016/0024-3205(93)90703-6

Cited by 73 publications

(56 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We, along with others, have hypothesized that glycosylation of smaller peptides may have desirable effects on the pharmacokinetic and/or pharmacodynamic properties of the parent peptide (Albert et al, 1993;Polt et al, 1994;Negri et al, 1998;Susaki et al, 1999;Suzuki et al, 1999a,b;Bilsky et al, 2000). More specifically, we have shown that O-linked glycosylation of a potent opioid hexapeptide does not interfere with the pharmacophore portion of the molecule, if the carbohydrate moiety is placed on the sixth amino acid residue (current results and Bilsky et al, 2000).…”

Section: Discussionmentioning

confidence: 56%

“…The addition of bulky transport vectors may also have adverse effects on peptide bioactivity, necessitating the incorporation of an enzymatic cleavage site into the transport vector to release the active peptide after transport (Rousselle et al, 2000). It is reasonable to hypothesize that glycosylation of a small peptide will increase the hydrophilicity, stability, and bioavailability of peptides (Albert et al, 1993;Polt et al, 1994;Negri et al, 1998;Bilsky et al, 2000). In studies investigating peptides and proteins that had been glycosylated nonspecifically via the Amidori reaction, an increase in delivery to both the peripheral and central nervous system was observed (Poduslo and Curran, 1994).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Elmagbari¹,

Egleton²,

Palian³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Development of opioid peptides as therapeutic agents has historically been limited due to pharmacokinetic issues including stability and blood-brain barrier (BBB) permeability. Glycosylation of opioid peptides can increase peptide serum stability and BBB penetration. To further define the requirements for optimizing in vivo antinociceptive potency following intravenous administration, we synthesized a series of enkephalin-based glycopeptides using solid phase 9-fluorenylmethyloxy carbamate methods. The compounds differed in the sixth and subsequent amino acid residues (Ser or Thr) and in the attached carbohydrate moiety. In vitro binding and functional smooth muscle bioassays indicated that the addition of mono-or disaccharides did not significantly affect the opioid receptor affinity or agonist activity of the glycopeptides compared with their unglycosylated parent peptides. All of the glycopeptides tested produced potent antinociceptive effects in male ICR mice following intracerebroventricular injection in the 55°C tail-flick test. The calculated A 50 values for the Ser/Thr and monosaccharide combinations were all very similar with values ranging from 0.02 to 0.09 nmol. Selected compounds were administered to mice intravenously and tested for antinociception to indirectly assess serum stability and BBB penetration. All compounds tested produced full antinociceptive effects with calculated A 50 values ranging from 2.2 to 46.4 mol/kg with the disaccharides having potencies that equaled or exceeded that of morphine on a micromoles per kilogram basis. Substitution of a trisaccharide or bis-and tris-monosaccharides resulted in a decrease in antinociceptive potency. These results provide additional support for the utility of glycosylation to increase central nervous system bioavailability of small peptides and compliment our ongoing stability and blood-brain barrier penetration studies.

show abstract

Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 99%

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Elmagbari¹,

Egleton²,

Palian³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…A fructose unit was appended to the R amino group of Lys 0 of this peptide via a Maillard reaction with glucose and subsequent Amadori rearrangement (23). The Fmoc group on the -amino group of Lys 0 was removed, and the resultant peptide was treated with either N-succinimidyl 3-iodobenzoate (SIB) or N-succinimidyl 3-(tri-n-butylstannyl)benzoate (STB).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Glycosylated Octreotate Analogues Labeled with Radioiodine and ²¹¹At via a Tin Precursor

Vaidyanathan

Schottelius

et al. 2005

Bioconjugate Chem.

View full text Add to dashboard Cite

Carbohydration of N-terminus and substitution of a threonine for the threoninol residue at the C-terminus of Tyr3-octreotide (TOC) has resulted in improved pharmacokinetics and tumor targeting of its radioiodinated derivatives. Yet, these peptides are very susceptible to in vivo deiodination due to the similarity of monoiodotyrosine (MIT) to thyroid hormone. The goal of this work was to develop octreotate analogues containing both a sugar moiety and a nontyrosine prosthetic group on which a radioiodine or 211At can be introduced. Solid-phase synthesis and subsequent modifications delivered an iodo standard of the target peptide N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-iodobenzoyl)-Lys0-octreotate (GIBLO) and the corresponding tin precursor N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate (GTBLO). GIBLO displaced [125I]TOC from somatostatin receptor subtype 2 (SSTR2)-positive AR42J rat pancreatic tumor cell membranes with an IC50 of 0.46 +/- 0.05 nM suggesting that GIBLO retained affinity to SSTR2. GTBLO was radiohalogenated to [131I]GIBLO and N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-[211At]astatobenzoyl)-Lys0-octreotate ([211At]GABLO) in 21.2 +/- 4.9% and 46.8 +/- 9.5% radiochemical yields, respectively. From a paired-label internalization assay using D341 Med medulloblastoma cells, the maximum specific internalized radioactivity from [131I]GIBLO was 1.78 +/- 0.8% of input dose compared to 9.67 +/- 0.43% for N(alpha)-(1-deoxy-D-fructosyl)-[125I]iodo-Tyr3-octreotate ([125I]I-Gluc-TOCA). Over a 4 h period, the extent of internalization of [131I]GIBLO and [211At]GABLO was similar in this cell line. In D341 Med murine subcutaneous xenografts, the uptake of [125I]I-Gluc-TOCA at 0.5, 1 and 4 h was 21.5 +/- 4.0% ID/g, 18.8 +/- 7.7% ID/g, and 0.9 +/- 0.4% ID/g, respectively. In comparison, these values for [131I]GIBLO were 6.9 +/- 1.2% ID/g, 4.7 +/- 1.4% ID/g, and 0.8 +/- 0.5% ID/g. Both in vitro and in vivo catabolism studies did not suggest the severance of the lys0 along with its appendages from the peptide. Taken together, although GIBLO maintained affinity to SSTR2, its tumor uptake both in vitro and in vivo was substantially lower than that of I-Gluc-TOCA suggesting other factors such as net charge and overall geometry of the peptide may be important.

show abstract

“…These results suggest that lactulosamines are most likely passively absorbed from ingested food. Of interest, the lactulosamine modification has been used to improve the bioavailability and stability of some drugs (111,112).…”

Section: Bioavailability Of Dietary Lactulosaminesmentioning

confidence: 99%

Food‐Related Carbohydrate Ligands for Galectins

2008

View full text Add to dashboard Cite

SDZ CO 611: a highly potent glycated analog of somatostatin with improved oral activity

Cited by 73 publications

References 12 publications

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Synthesis and Evaluation of Glycosylated Octreotate Analogues Labeled with Radioiodine and ²¹¹At via a Tin Precursor

Food‐Related Carbohydrate Ligands for Galectins

Contact Info

Product

Resources

About

SDZ CO 611: a highly potent glycated analog of somatostatin with improved oral activity

Cited by 73 publications

References 12 publications

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Synthesis and Evaluation of Glycosylated Octreotate Analogues Labeled with Radioiodine and 211At via a Tin Precursor

Food‐Related Carbohydrate Ligands for Galectins

Contact Info

Product

Resources

About

Synthesis and Evaluation of Glycosylated Octreotate Analogues Labeled with Radioiodine and ²¹¹At via a Tin Precursor