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1.
J Med Chem ; 40(15): 2386-97, 1997 Jul 18.
Article in English | MEDLINE | ID: mdl-9240353

ABSTRACT

The pentapeptide, thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5) is known for its activity as an immunomodulating drug, but with limited half-life in plasma. In this first paper of a series of three studies, the synthesis of analogs stabilized at the peptide bond between the C-terminal amino acids via insertion of a ketomethylene moiety is described. N-Blocked pseudopeptides containing Val(k)Phe, Ala(k)Phe, and Val(k)Val units were prepared and attached to chloromethyl Merrifield resin via the carboxy terminal. Removal of the N-BOC group by trifluoroacetic acid was followed by sequential coupling with N-BOC dipeptides of aspartic acid to yield resin-bound N-BOC pseudotetrapeptides. Removal of N-BOC and coupling with N-BOC-r-N-tosylarginine followed by total cleavage of blocking groups and resin by HF afforded the target pseudopentapeptides. The analogs were found to compete favorably with thymopentin for binding to CEM cells, but binding was reduced by about 20-30% on average. All analogs showed significant enhancement of half-life versus thymopentin in mouse serum, but most showed only modest improvement in human serum. Insertion of proline or norleucine at position 2 in the chain caused a substantial increase in half-life (3-4-fold), while N-methylnorleucine conferred complete stability in the analogs.


Subject(s)
Adjuvants, Immunologic/chemistry , Ketones/chemistry , Oligopeptides/chemistry , Thymopentin/analogs & derivatives , Adjuvants, Immunologic/blood , Adjuvants, Immunologic/pharmacology , Animals , Cell Line , Half-Life , Humans , Magnetic Resonance Spectroscopy , Mice , Radioligand Assay , Spectrometry, Mass, Fast Atom Bombardment , Structure-Activity Relationship , Thymopentin/blood , Thymopentin/pharmacology
2.
J Med Chem ; 40(15): 2398-406, 1997 Jul 18.
Article in English | MEDLINE | ID: mdl-9240354

ABSTRACT

In this second paper in a series of three studies of stable analogs of thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5), the synthesis of analogs stabilized at peptide bonds 1,2 and 3,4 via insertion of ketomethylene units is described. A tris(carbobenzyloxy)arginyl(k)norleucine pseudopeptide was synthesized and coupled to Asp-Val-Phe-resin units followed by HF cleavage to prepare Arg(k)Nle-Asp-Val-Phe analogs. Preparation of N-BOC Asp(k)Val and N-BOC Asp(k)Ala units followed by coupling to Phe- or Tyr-resin units provided resin-bound pseudotripeptide substrates for attachment of various arginyl dipeptides. Cleavage from the resin afforded 3,4-ketomethylene-stabilized pseudopeptide analogs of thymopentin. The Arg-Lys-Asp(k)Val-Phe and Arg-Lys-Asp(k)Val-Tyr analogs were more strongly bound to CEM cells than thymopentin itself. There was significant enhancement of stability in serum for the analogs, especially those containing Arg(k)Nle or Arg-NMeLys moieties at the 1,2-peptide bond.


Subject(s)
Adjuvants, Immunologic/chemistry , Ketones/chemistry , Oligopeptides/chemistry , Thymopentin/analogs & derivatives , Adjuvants, Immunologic/blood , Adjuvants, Immunologic/pharmacology , Animals , Drug Stability , Half-Life , Humans , Isomerism , Magnetic Resonance Spectroscopy , Mice , Radioligand Assay , Spectrometry, Mass, Fast Atom Bombardment , Thymopentin/blood , Thymopentin/pharmacology
3.
Biochem Biophys Res Commun ; 175(3): 886-93, 1991 Mar 29.
Article in English | MEDLINE | ID: mdl-1850994

ABSTRACT

An endopeptidase isolated from bovine kidney displays high affinity and selectivity for the Ser-Phe bond located in the C-terminal region of atrial peptides. Enzymatic activity converts APIII and APII to the less active peptide API. This peptidase is inhibited by both metal chelators and sulfhydryl-reactive agents, suggesting both a tightly bound metal and a cysteine residue are important for enzymatic activity. This enzyme may be important for the processing and/or degradation of atrial peptides.


Subject(s)
Atrial Natriuretic Factor/metabolism , Endopeptidases/metabolism , Kidney Cortex/enzymology , Amino Acid Sequence , Animals , Biotransformation , Cattle , Chromatography/methods , Chromatography, DEAE-Cellulose/methods , Chromatography, Gel/methods , Durapatite , Endopeptidases/isolation & purification , Hydroxyapatites , Kinetics , Molecular Sequence Data , Molecular Weight , Oligopeptides/metabolism , Protease Inhibitors/pharmacology , Substrate Specificity
4.
Int J Pept Protein Res ; 34(6): 455-62, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2635691

ABSTRACT

A series of 20 peptide analogs of (des-Glu1)conotoxin GI were prepared by solid phase synthesis. The peptides were tested for their abilities to inhibit contractions in the mouse-diaphragm-with-phrenic-nerve assay. (Des-Glu1)conotoxin has an IC50 of 2.7 x 10(-7) M in this assay. Results from this assay show that total loss of paralytic activity occurs when Pro is replaced by Gly, Tyr by D-Tyr, or Gly by D-Phe. In most cases loss or change in length of one of the disulfide rings eliminates paralytic activity except with compound 17, which is weakly active, IC50 = 7.0 x 10(-5) M. Replacement of the Cys1-Cys6 disulfide bond with an amide bond (compound 9) greatly lowers paralytic activity, IC50 = 3.7 x 10(-5) M.


Subject(s)
Conotoxins , Mollusk Venoms/toxicity , Neuromuscular Junction/drug effects , Paralysis/chemically induced , Amino Acid Sequence , Animals , Diaphragm/drug effects , In Vitro Techniques , Male , Mice , Molecular Sequence Data , Mollusk Venoms/chemical synthesis , Rats , Structure-Activity Relationship
5.
J Med Chem ; 31(3): 561-7, 1988 Mar.
Article in English | MEDLINE | ID: mdl-2831364

ABSTRACT

Two ketomethylene-containing nonapeptide analogues were synthesized to determine if ketomethylene analogues of the nonapeptide venom inhibitors of angiotensin converting enzyme (ACE) would have oral ACE inhibition activity. Both ketomethylene-containing nonapeptides 18 and 19 were potent inhibitors of rabbit lung ACE with I50s of 3.4 and 8.0 nM, respectively, compared to 340 nM for their parent nonapeptide and 450 nM for captopril. Peptide 18 was rapidly cleaved by trypsin, but 19 was reasonably stable to all enzyme degradation systems tested with maximum degradation of 50% by pepsin in 3 h. Both 18 and 19 when given iv to normotensive rats were between 3 and 10 times more potent than captopril in inhibiting an angiotensin I induced blood pressure increase. Peptide 19 showed no ACE inhibition activity in unanesthetized normotensive rats when administered orally at doses of 10 or 100 mg/kg. Experiments were conducted to determine whether 19 is adsorbed from the gastrointestinal track following oral administration. These experiments indicated that 19 is adsorbed. It is concluded that the lack of oral activity of 19 is probably due to its rapid excretion, probably into the bile.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Oligopeptides/chemical synthesis , Snake Venoms , Animals , Captopril/pharmacology , Chemical Phenomena , Chemistry, Physical , Kinetics , Lung/enzymology , Oligopeptides/pharmacology , Peptidyl-Dipeptidase A/metabolism , Rabbits , Structure-Activity Relationship
6.
Biochem Biophys Res Commun ; 135(3): 770-7, 1986 Mar 28.
Article in English | MEDLINE | ID: mdl-3008745

ABSTRACT

Ketomethylene containing peptide analogs, modeled after a snake venom pentapeptide, have been shown to be potent angiotensin converting enzyme inhibitors. Although the most potent compounds are up to five times more potent than captopril in inhibiting angiotensin converting enzyme activity, they are relatively weak inhibitors of [3H]captopril binding to membrane bound angiotensin converting enzyme. This indicates that inhibition of [3H]captopril binding and enzymatic activity is due to binding to distinct sites. These results suggest that the inhibitors bind to an additional site on the enzyme distinct from the captopril binding site.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Captopril/metabolism , Animals , Binding Sites , Kinetics , Lung/enzymology , Male , Peptidyl-Dipeptidase A/metabolism , Rats
7.
J Med Chem ; 28(8): 1062-6, 1985 Aug.
Article in English | MEDLINE | ID: mdl-2991517

ABSTRACT

Two pentapeptide analogues of the ketomethylene-containing angiotensin converting enzyme (ACE) inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and evaluated as ACE inhibitors and antihypertensive agents. Compounds 14 and 15 were very potent ACE inhibitors with I50 values of 7.0 and 3.0 nM, respectively, compared to an I50 value of 70 nM for 1. Neither 14 nor 15 showed significant blood pressure lowering activity in renal hypertensive rats. Investigations conducted on a tritiated analogue of 14 showed that 70% of an oral dose of this compound is absorbed but is rapidly excreted from the blood with a half life of 24 min. Thin-layer chromatography of bile and urine contents in rats given tritiated 14 orally showed that it is excreted in greater than 90% unchanged form. This implies that a ketomethylene linkage can stabilize peptide amide linkages adjacent to it to peptidase degradation.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Antihypertensive Agents/chemical synthesis , Dipeptides/pharmacology , Animals , Dipeptides/chemical synthesis , Dipeptides/metabolism , Hypertension, Renovascular/drug therapy , Male , Metabolic Clearance Rate , Rats , Rats, Inbred Strains , Structure-Activity Relationship
8.
J Med Chem ; 28(8): 1067-71, 1985 Aug.
Article in English | MEDLINE | ID: mdl-2991518

ABSTRACT

The carboxylic acid group on the proline of 1 was replaced by a phosphoric acid, a hydroxamic acid, and a tetrazole to give compounds 2-4, respectively. Testing of 2-4 as angiotensin converting enzyme (ACE) inhibitors gave I50 values of 100, 1.6, and 22 microM, respectively, compared to 0.07 microM for 1. A hydroxamic acid derivative of the ketomethylene pentapeptide analogue 18 was then synthesized. This compound, 17, had an ACE I50 of 0.011 microM compared to 0.0076 microM for 18. Oral administration of 10 mg/kg of 17 to renal hypertensive rats had no effect on blood pressure or heart rate.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Antihypertensive Agents/chemical synthesis , Dipeptides/pharmacology , Animals , Dipeptides/chemical synthesis , Dipeptides/metabolism , Hypertension, Renovascular/drug therapy , Rats , Structure-Activity Relationship
9.
Life Sci ; 37(4): 299-305, 1985 Jul 29.
Article in English | MEDLINE | ID: mdl-2989647

ABSTRACT

Tritium and Carbon 14 analogs of the angiotensin converting enzyme inhibitor ketoACE were synthesized and their oral absorption, metabolism and excretion in rats were investigated. KetoACE, a ketomethylene analog of the tripeptide Bz-Phe-Gly-Pro, was slowly absorbed at a 35% level upon oral administration. It is rapidly eliminated from the blood with a half-life of about 10 minutes. Its excretion is primarily via the bile duct and it is excreted as 80% unchanged drug. The only identified metabolite consisting of 5-10% of the excreted radioactivity was determined to be the reduced ketoACE in which the ketone group was reduced to a hydroxyl.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Dipeptides/metabolism , Animals , Bile/metabolism , Carbon Radioisotopes , Half-Life , Male , Rabbits , Rats , Rats, Inbred Strains , Tritium
10.
J Med Chem ; 27(2): 115-20, 1984 Feb.
Article in English | MEDLINE | ID: mdl-6319699

ABSTRACT

A peptide analogue of Leu-enkephalin was synthesized in which the amide linkages between Tyr-Gly and Gly-Gly were replaced by ketomethylene groups. The resulting analogue, 12, had 1/4000th and 1/2400th the opiate receptor binding activity of Leu-enkephalin when (3H) [D-Ala2,D-Leu5]enkephalin and (3H)naloxone, respectively, were used as tritiated ligands. When tested for analgesia in mice by the tail-flick assay, 12 produced analgesia in 50% of the mice tested at a dose of 24.3 micrograms/mouse (icv), while the ED50 of Leu-enkephalin is 240 micrograms/mouse (icv). At a dose of 40 micrograms/mouse (icv) or higher, 12 caused convulsions in a dose-dependent manner. No analgesia was observed after intravenous (iv) administration of 240 micrograms/mouse of 12.


Subject(s)
Enkephalin, Leucine/analogs & derivatives , Glycine , Tyrosine , Analgesia , Animals , Biological Assay , Chemical Phenomena , Chemistry , Dose-Response Relationship, Drug , Enkephalin, Leucine/metabolism , Mice , Receptors, Opioid/metabolism , Seizures/chemically induced , Structure-Activity Relationship
12.
J Pharm Sci ; 72(1): 63-7, 1983 Jan.
Article in English | MEDLINE | ID: mdl-6298401

ABSTRACT

An amino analogue of N-benzoyl-phenylalanyl-glycyl-proline, a tripeptide inhibitor of angiotensin-converting enzyme, was synthesized. The analogue (III) has the phenylalanyl-glycine amide linkage of N-benzoyl-phenylalanyl-glycyl-proline reduced to a methylene amine. Compound III was tested as an inhibitor of porcine plasma angiotensin-converting enzyme and has an I50 of 620 microM compared with an I50 of 9.6 microM for its parent tripeptide. These results are explained in terms of a proposed model of the converting-enzyme active site.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Oligopeptides/chemical synthesis , Animals , Binding Sites , Chemical Phenomena , Chemistry , In Vitro Techniques , Kinetics , Oligopeptides/pharmacology , Peptidyl-Dipeptidase A/blood , Swine
13.
J Med Chem ; 25(11): 1292-9, 1982 Nov.
Article in English | MEDLINE | ID: mdl-6292422

ABSTRACT

Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Dipeptides/chemical synthesis , Animals , Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Dipeptides/pharmacology , Guinea Pigs , Heart Rate/drug effects , Hypertension, Renal/drug therapy , Male , Rats , Structure-Activity Relationship
14.
J Med Chem ; 24(8): 964-9, 1981 Aug.
Article in English | MEDLINE | ID: mdl-6173481

ABSTRACT

A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.


Subject(s)
Dipeptides/chemical synthesis , Oligopeptides , Angiotensin II/metabolism , Animals , Blood Pressure/drug effects , Dipeptides/pharmacology , Dose-Response Relationship, Drug , Male , Rats , Structure-Activity Relationship , Teprotide
15.
J Med Chem ; 23(12): 1392-8, 1980 Dec.
Article in English | MEDLINE | ID: mdl-6256550

ABSTRACT

An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM, than Bz-Phe-Gly-Pro, I50 = 9.4 microM, or than the orally active D-3-mercapto-2-methylpropanoyl-L-proline (captopril, 1), I50 = 0.30 microM. Compound 20 has a Ki of 1.06 X 10(-7) and either competitive or noncompetitive enzyme kinetics depending on what substrate is used in the converting enzyme assay. In tests for inhibition of angiotensin I induced contractions in the guinea pig ileum, 20 has one-tenth the activity of 1.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Dipeptides/chemical synthesis , Angiotensin I/antagonists & inhibitors , Animals , Chemical Phenomena , Chemistry , Dipeptides/pharmacology , Guinea Pigs , In Vitro Techniques , Kinetics , Male , Muscle Contraction/drug effects
16.
J Med Chem ; 20(10): 1246-50, 1977 Oct.
Article in English | MEDLINE | ID: mdl-903916

ABSTRACT

Nitrosourea derivatives of sucrose have been synthesized for the purpose of obtaining anticancer agents with activity against brain cancer. Two such compounds, 6,6'-dideoxy-6,6'-di(3-methyl-3-nitrosoureido) sucrose (13) and 1', 6,6'-trideoxy-1',6,6-tri(3-methyl-3-nitrosoureido) sucrose (14), and their respective acetylated derivatives 15 and 16 have been prepared from sucrose. Compounds 13 and 14 have demonstrated antitumor activity against both L1210 leukemia and ependymoblastoma brain tumor in mice.


Subject(s)
Antineoplastic Agents/chemical synthesis , Brain Neoplasms/drug therapy , Nitrosourea Compounds/chemical synthesis , Sucrose/analogs & derivatives , Animals , Antineoplastic Agents/therapeutic use , Ependymoma/drug therapy , Leukemia L1210/drug therapy , Mice , Mice, Inbred Strains , Neoplasms, Experimental/drug therapy , Nitrosourea Compounds/pharmacology , Nitrosourea Compounds/therapeutic use , Sucrose/chemical synthesis , Sucrose/pharmacology , Sucrose/therapeutic use
18.
Antimicrob Agents Chemother ; 8(4): 439-43, 1975 Oct.
Article in English | MEDLINE | ID: mdl-1103725

ABSTRACT

The effect of a series of puromycin analogues and aminoacyl chloramphenicol derivatives on poly(U,C)-directed polyphenylalanine synthesis in an Escherichia coli cell-free system was examined. A comparison between the structures and activities of the puromycin and chloramphenicol analogues was made to examine the proposal that ribosomal binding sites for both antibiotics overlap. Our results suggest that the dichloroacetamido group in the chloramphenicol molecule does not correspond to the role of the aminoacyl moieties of either puromycin or aminoacyl transfer ribonucleic acid. These results comparing the structures and activities of puromycin and chloramphenicol analogues also seem inconsistent with a common binding site for the p-substituted phenyl moieties of the two antibiotics. Previous data have indicated that both sites are mutually affected by the prior binding of either antibiotic. Although it is possible that chloramphenicol and puromycin may have overlapping bindings sites, no common structural features between the two antibiotics are supported by our data.


Subject(s)
Binding Sites/drug effects , Chloramphenicol/analogs & derivatives , Chloramphenicol/pharmacology , Puromycin/analogs & derivatives , Cell-Free System , Escherichia coli/metabolism , Peptide Chain Initiation, Translational/drug effects , Phenylalanine/biosynthesis , Puromycin/pharmacology , Structure-Activity Relationship/drug effects
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