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1.
J Antibiot (Tokyo) ; 51(8): 722-34, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9766464

ABSTRACT

A systematic approach toward building activity against methicillin-resistant staphylococci into the cephalosporin class of beta-lactam antibiotics is described. Initial work focused on finding the optimal linkage between the cephem nucleus and a biphenyl pharmacophore, which established that a thio linkage afforded potent activity in vitro. Efforts to optimize this activity by altering substitution on the pharmacophore afforded iodophenylthio analog MC-02,002, which although highly potent against MRSA, was also highly bound to serum proteins. Further work to decrease serum protein binding showed that replacement of the iodo substituent by the positively-charged isothiouronium group afforded potent activity and reduced serum binding, but insufficient aqueous solubility. Solubility was enhanced by incorporation of a second positively-charged group into the 7-acyl substituent. Such derivatives (MC-02,171 and MC-02,306) lacked sufficient stability to staphylococcal beta-lactamase enzymes. The second positive charge was incorporated into the cephem 3-substituent in order to utilize the beta-lactamase-stable aminothiazolyl(oximino)acetyl class of 7-substituents. These efforts culminated with the discovery of bis(isothiouroniummethyl)phenylthio analog MC-02,331, whose profile is acceptable with respect to potency against MRSA, serum binding, aqueous solubility, and beta-lactamase stability.


Subject(s)
Bacterial Proteins , Cephalosporins/chemistry , Hexosyltransferases , Lactams/chemistry , Peptidyl Transferases , Staphylococcus aureus/drug effects , Animals , Carrier Proteins/metabolism , Cephalosporins/metabolism , Cephalosporins/pharmacology , Humans , Lactams/metabolism , Lactams/pharmacology , Male , Methicillin Resistance , Mice , Microbial Sensitivity Tests , Muramoylpentapeptide Carboxypeptidase/metabolism , Penicillin-Binding Proteins , Structure-Activity Relationship
2.
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
3.
J Med Chem ; 40(3): 370-6, 1997 Jan 31.
Article in English | MEDLINE | ID: mdl-9022804

ABSTRACT

Carbonation of the dianions (LDA) of 5-methylthiophene-2-carboxylic, 2-methylpyridine-5-carboxylic, and 3-methylpyridine-6-carboxylic acids provided the respective carboxy heteroarylacetic acids. The crude diacids were directly esterified in MeOH-HCl to afford the diesters. Alkylation of the sodio anions with ethyl iodide yielded the appropriate alpha-ethyl diesters. The anions of the various diester substrates were then alkylated by 2,4-diamino-6-(bromomethyl)-pteridine followed by ester saponification at room temperature to afford the respective 2,4-diamino-4-deoxy-10-carboxy-10-deazapteroic acids. The 10-carboxyl group was readily decarboxylated by heating in DMSO at temperatures of 110-135 degrees C to give the diamino 10-deaza heteropteroic acid intermediates. Coupling with diethyl L-glutamate followed by ester hydrolysis afforded the target aminopterins. The analogues were evaluated for antiinflammatory effect in the mouse type II collagen model. The thiophene analogue of 10-ethyl-10-deazaaminopterin was found to be an effective inhibitor in terms of reduced visual evidence of inflammation and swelling as determined by caliper measurement.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Methotrexate/analogs & derivatives , Aminopterin , Animals , Antirheumatic Agents/chemical synthesis , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Cell Line , Cell Survival/drug effects , Collagen , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Methotrexate/chemistry , Methotrexate/pharmacology , Methotrexate/therapeutic use , Mice , Molecular Structure , Tumor Cells, Cultured
4.
Metabolism ; 37(5): 411-7, 1988 May.
Article in English | MEDLINE | ID: mdl-3285129

ABSTRACT

Intermediary metabolite and serum insulin concentrations have been measured during incremental intravenous low-dose insulin infusion in massively obese patients before, and 3 months and 12 months after gastroplasty. Fasting blood glucose was similar on the three occasions, but fasting serum insulin was significantly higher preoperatively and showed a progressive fall with weight loss. Significant negative linear correlations were found between serum insulin and blood glucose, plasma nonesterified fatty acids, blood glycerol and blood total ketone bodies concentrations. The insulin-glucose dose-response curve showed a significant left shift at 3 months with a further significant improvement at 12 months. No significant change in the responses for nonesterified fatty acids, glycerol, and ketone bodies was observed at 3 months, but all three showed a significant left shift at 12 months. Massively obese patients are resistant to the action of insulin on carbohydrate and fat metabolism. Weight loss following gastroplasty results in an improvement in sensitivity to insulin, which is evident earlier in carbohydrate metabolism than in fat metabolism.


Subject(s)
Body Weight , Glucose/metabolism , Insulin Resistance , Lipid Metabolism , Obesity, Morbid/metabolism , Adult , Blood Glucose/analysis , Fatty Acids, Nonesterified/blood , Female , Glycerol/blood , Humans , Insulin/blood , Ketone Bodies/metabolism , Male , Middle Aged , Regression Analysis
5.
FEBS Lett ; 217(1): 106-10, 1987 Jun 08.
Article in English | MEDLINE | ID: mdl-3109940

ABSTRACT

The binding of folate to Lactobacillus casei dihydrofolate reductase in the presence and absence of NADP+ has been studied by 15N NMR, using [5-15N]folate. In the presence of NADP+, three separate signals were observed for the single 15N atom, in agreement with our earlier evidence from 1H and 13C NMR for multiple conformations of this complex [(1982) Biochemistry 21, 5831-5838]. The 15N spectra of the binary enzyme-folate complex provide evidence for the first time that this complex also exists in at least two conformational states. This is confirmed by the observation of two separate resonances for the 7-proton of bound folate, located by two-dimensional exchange spectroscopy.


Subject(s)
Bacterial Proteins/metabolism , Folic Acid/metabolism , Tetrahydrofolate Dehydrogenase/metabolism , Hydrogen-Ion Concentration , Lacticaseibacillus casei/enzymology , Magnetic Resonance Spectroscopy , NADP/metabolism , Protein Binding , Protein Conformation
6.
Arch Dis Child ; 61(4): 341-5, 1986 Apr.
Article in English | MEDLINE | ID: mdl-3518640

ABSTRACT

Metabolic rhythms were studied over 24 hours in eight adolescent diabetic patients during treatment with porcine insulin and after transfer to human insulin. Despite an increase in dose with human insulin no significant changes were found in fasting blood glucose, 24h mean blood glucose, or glycosylated haemoglobin concentrations. Significantly higher 24h mean blood lactate concentrations and lower total ketone bodies and glycerol concentrations were observed during treatment with human insulin. These findings are consistent with the increase in insulin dose and do not necessarily imply different metabolic responses to species differences in insulin.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Insulin/therapeutic use , Adolescent , Animals , Blood Glucose/metabolism , Child , Diabetes Mellitus, Type 1/blood , Drug Administration Schedule , Female , Glycerol/blood , Humans , Insulin/administration & dosage , Insulin, Isophane/therapeutic use , Insulin, Regular, Pork , Ketone Bodies/blood , Lactates/blood , Lactic Acid , Male , Pyruvates/blood , Pyruvic Acid
7.
Diabete Metab ; 12(2): 74-8, 1986 Apr.
Article in English | MEDLINE | ID: mdl-3522299

ABSTRACT

The response of intermediary metabolite concentrations was measured in six insulin-dependent diabetic men during intravenous low-dose incremental insulin infusion. Insulin was infused during consecutive hours at rates of 0.01 u/kg/h, 0.05 u/kg/h and 0.10 u/kg/h. Each patient was studied on two occasions a month apart using either highly purified porcine or semi-synthetic human short-acting insulin. No difference was observed in the changes in blood glucose, lactate, pyruvate, glycerol, alanine, total ketone bodies or plasma non-esterified fatty acids. Thus no difference could be identified in the actions of intravenous porcine and semi-synthetic human insulin on carbohydrate, fat or ketone body metabolism in vivo.


Subject(s)
Diabetes Mellitus, Type 1/blood , Insulin Infusion Systems , Adult , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/drug therapy , Fatty Acids, Nonesterified/blood , Humans , Insulin/administration & dosage , Insulin/blood , Insulin, Regular, Pork , Ketone Bodies/blood , Male
8.
Article in English | MEDLINE | ID: mdl-3758049

ABSTRACT

The metabolic and hormonal response during squash was observed in eight normal men. Significant increases from resting were found for blood glucose, lactate, pyruvate, alanine and glycerol while total ketone bodies and plasma nonesterified fatty acids rose after play stopped. Insulin and C-peptide decreased significantly and catecholamines, ACTH, prolactin and growth hormone increased.


Subject(s)
Hormones/blood , Metabolism , Physical Exertion , Adult , Blood Glucose/analysis , Humans , Lactates/blood , Male , Pyruvates/blood
9.
Br Med J (Clin Res Ed) ; 289(6451): 1035-8, 1984 Oct 20.
Article in English | MEDLINE | ID: mdl-6091840

ABSTRACT

The effect of intravenous bicarbonate on the changes in intermediary metabolites during the initial treatment of diabetic ketoacidosis was examined in 16 patients. The results were compared with the changes seen in 16 patients receiving intravenous saline. Infusion of 150 mmol (mEq) bicarbonate significantly delayed the fall in blood lactate, lactate:pyruvate ratio, and total ketone bodies observed in the saline treated group. No difference in the rate of fall of blood glucose concentration was found. There is no metabolic indication for the use of intravenous bicarbonate in the treatment of diabetic ketoacidosis.


Subject(s)
Bicarbonates/therapeutic use , Diabetic Ketoacidosis/drug therapy , Adolescent , Adult , Aged , Blood Glucose/metabolism , Diabetic Ketoacidosis/blood , Female , Humans , Ketone Bodies/blood , Lactates/blood , Male , Middle Aged , Pyruvates/blood , Sodium Bicarbonate , Sodium Chloride/therapeutic use
10.
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
11.
J Med Chem ; 21(5): 415-22, 1978 May.
Article in English | MEDLINE | ID: mdl-207868

ABSTRACT

A series of N-sec- and N-tert-alkylnormorphines was synthesized and evaluated for analgesic potency, antagonist activity, and opiate receptor binding. Computer-assisted conformational analysis profiles were utilized to assist in the selection of compounds for synthesis and correlation of receptor events with in vivo observations. N-tert-Alkylnormorphines 5a-c were devoid of agonist activity; however, some sec-alkyl analogues showed interesting mixed agonist-antagnoist actions. N-sec-Butyl- and N-(alpha-methylally)normorphine were separated into R and S isomers, which exhibited quantitative pharmacological differences. The N-sec-butyl S isomer 10a showed analgesia approximating morphine with nalorphine-like antagonist activity. Preliminary testing indicates only slight evidence for physical dependence with this compound.


Subject(s)
Analgesics/chemical synthesis , Morphine Derivatives/chemical synthesis , Animals , Brain/metabolism , In Vitro Techniques , Male , Methods , Mice , Molecular Conformation , Morphine/antagonists & inhibitors , Morphine Derivatives/metabolism , Morphine Derivatives/pharmacology , Rats , Reaction Time/drug effects , Receptors, Opioid/metabolism , Structure-Activity Relationship , Thermodynamics
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