scholarly journals Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

2000 ◽  
Vol 345 (2) ◽  
pp. 351-356 ◽  
Author(s):  
Corie N. SHRIMPTON ◽  
Giovanni ABBENANTE ◽  
Rebecca A. LEW ◽  
A. Ian SMITH
Keyword(s):  
Potent Inhibitor ◽  
Solid Phase ◽  
Neutral Endopeptidase ◽  
Amide Bond ◽  
Converting Enzyme ◽  
Phase Synthesis ◽  
Tissue Extracts ◽  
Endothelin Converting Enzyme

Solid-phase synthesis was used to prepare a series of modifications to the selective and potent inhibitor of endopeptidase EC 3.4.24.15 (EP24.15), N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), which is degraded at the Ala-Tyr bond, thus severely limiting its utility in vivo. Reducing the amide bond between the Ala and Tyr decreased the potency of the inhibitor to 1/1000. However, the replacement of the second alanine residue immediately adjacent to the tyrosine with α-aminoisobutyric acid gave a compound (JA-2) that was equipotent with cFP, with a Ki of 23 nM. Like cFP, JA-2 inhibited the closely related endopeptidase EC 3.4.24.16 1/20 to 1/30 as potently as it did EP24.15, and did not inhibit the other thermolysin-like endopeptidases angiotensin-converting enzyme, endothelin-converting enzyme and neutral endopeptidase. The biological stability of JA-2 was investigated by incubation with a number of membrane and soluble sheep tissue extracts. In contrast with cFP, JA-2 remained intact after 48 h of incubation with all tissues examined. Further modifications to the JA-2 compound failed to improve the potency of this inhibitor. Hence JA-2 is a potent, EP24.15-preferential and biologically stable inhibitor, therefore providing a valuable tool for further assessing the biological functions of EP24.15.

scholarly journals Endopeptidase 3.4.24.11 converts N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide into a potent inhibitor of angiotensin-converting enzyme

1993 ◽  
Vol 294 (3) ◽  
pp. 681-684 ◽  
Author(s):  
C H Williams ◽  
T Yamamoto ◽  
D M Walsh ◽  
D Allsop
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Potent Inhibitor ◽  
Neutral Endopeptidase ◽  
Converting Enzyme ◽  
Inhibitory Effects ◽  
Rabbit Lung ◽  
Pig Kidney ◽  
Tissue Extracts ◽  
Ic50 Value

It was reported recently that N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide (CPP-A-A-F-pAB), an inhibitor of endopeptidase 3.4.24.15 (E-24.15), also inhibits angiotensin-converting enzyme (ACE) from rabbit lung. We have found that this compound is without effect on ACE purified from pig kidney, at a concentration some 1000-fold greater than the Ki reported for inhibition of the enzyme from lung. However, preincubation of CPP-A-A-F-pAB with neutral endopeptidase 3.4.24.11 (E-24.11) does result in potent inhibitory effects on ACE. We have shown this to be due to formation of a fragment, CPP-A-A, the structure of which is closely related to ACE inhibitors such as enalaprilat. CPP-A-A was found to be a potent inhibitor of pig ACE. Under the conditions used it had an IC50 value of 1.6 x 10(-8) M, compared with the value obtained for captopril of 7.5 x 10(-10) M. These results have important implications for studies of E-24.15 when using CPP-A-A-F-pAB in vivo or in crude tissue extracts where E-24.11 might also be present.

In vivo characterization of a phosphoramidon-sensitive endothelin-converting enzyme in the rat

1993 ◽  
Vol 231 (3) ◽  
pp. 459-464 ◽  
Author(s):  
David M. Pollock ◽  
Barbara J. Divish ◽  
Ivan Milicic ◽  
Eugene I. Novosad ◽  
Neal S. Burres ◽  
...  
Keyword(s):  
Converting Enzyme ◽  
Endothelin Converting Enzyme ◽  
In Vivo Characterization

Solid phase synthesis of phosphinic acid endothelin converting enzyme inhibitors

1996 ◽  
Vol 6 (12) ◽  
pp. 1323-1326 ◽  
Author(s):  
John Lloyd ◽  
Joan B. Schmidt ◽  
John T. Hunt ◽  
Joel C. Barrish ◽  
Deborah K. Little ◽  
...  
Keyword(s):  
Solid Phase Synthesis ◽  
Enzyme Inhibitors ◽  
Solid Phase ◽  
Phosphinic Acid ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Phase Synthesis ◽  
Endothelin Converting Enzyme

Oxytocin analogues with non-coded amino acid residues in position 8: [8-Neopentylglycine]oxytocin and [8-cycloleucine]oxytocin

1987 ◽  
Vol 52 (9) ◽  
pp. 2317-2325 ◽  
Author(s):  
Jan Hlaváček ◽  
Jan Pospíšek ◽  
Jiřina Slaninová ◽  
Walter Y. Chan ◽  
Victor J. Hruby
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
The Other ◽  
Amino Acid Residues ◽  
Phase Synthesis ◽  
Other Hand ◽  
Fragment Condensation

[8-Neopentylglycine]oxytocin (II) and [8-cycloleucine]oxytocin (III) were prepared by a combination of solid-phase synthesis and fragment condensation. Both analogues exhibited decreased uterotonic potency in vitro, each being about 15-30% that of oxytocin. Analogue II also displayed similarly decreased uterotonic potency in vivo and galactogogic potency. On the other hand, analogue III exhibited almost the same potency as oxytocin in the uterotonic assay in vivo and in the galactogogic assay.

scholarly journals Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 197
Author(s):  
Iván Ramos-Tomillero ◽  
Marisa K. Sánchez ◽  
Hortensia Rodríguez ◽  
Fernando Albericio
Keyword(s):  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Structural Features ◽  
Amide Bond ◽  
Acidic Media ◽  
Phase Synthesis ◽  
Acyl Chains ◽  
Cyclic Compounds ◽  
Relationship Of ◽  
Fine Tune

Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated α,α-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated α,α-dialkylglycine amides 1a–n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.

Total solid-phase synthesis, purification and characterization of human parathyroid hormone-(1-84)

Biochemistry ◽  
1983 ◽  
Vol 22 (11) ◽  
pp. 2691-2697 ◽  
Author(s):  
T. Fairwell ◽  
A. V. Hospattankar ◽  
R. Ronan ◽  
H. B. Brewer ◽  
J. K. Chang ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Total Solid ◽  
Human Parathyroid Hormone ◽  
Purification And Characterization ◽  
Phase Synthesis
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