Synthesis and hypoglycemic activity of phenylalkyloxiranecarboxylic acid derivatives

Eistetter, Klaus; Wolf, H. P. O.

doi:10.1021/jm00344a003

Cited by 40 publications

(17 citation statements)

References 11 publications

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“…In this study, a selected potent agent of a new class of hypoglycaemic compounds [11] is shown to produce a dose-dependent decrease of glucose and ketone bodies in several normal and diabetic animals. Since B 807-27 has the same potency as its ester B 807-06, and no significant difference exists between per os and IV administration, it seems likely that the anion of B 807-27 is the active compound reaching the site of action in the target tissues.…”

Section: Discussionmentioning

confidence: 96%

Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: Hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals

1982

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Summary.Phenylalkyloxirane carboxylic acids and esters are a new class of potent hypoglycaemic substances. Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) produces a dosedependent hypoglycaemic effect when administered orally or intravenously to several fasted laboratory animals, i.e. rats (with and without adrenalectomy), guinea pigs, dogs, streptozotocin-treated diabetic pigs and db/db-mice. In addition, the substances have a more pronounced lowering effect on ketone bodies in the blood than any other known substance. The minimal dose for lowering blood glucose significantly in rats is 15 gmol/kg. The corresponding dose for a significant lowering of ketone bodies in the blood is < 2.4 lxmol/kg. Hence, the substance B 807-27 is approximately five times more potent than tolbutamide and 30 times more potent than the biguanide buformin with respect to lowering blood glucose levels. B 807-27 differs from the sulphonylureas in that it fails to stimulate insulin secretion. In contrast to the biguanides, the substance decreases rather than increases blood lactate concentration and blocks both fatty acid oxidation and gluconeogenesis. The therapeutic usefulness of these compounds in diabetic man remains to be elucidated.

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Section: Discussionmentioning

confidence: 96%

Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: Hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals

1982

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“…Inhibition of fatty acid oxidation is associated with reduced hyperglycemia due to inhibition of glucose production [35,40]. Most of the investigational CPT-1 inhibitors have been shown to cause hypoglycemia and some also cause hypoketonemia [121].…”

Section: Oxfenicinementioning

confidence: 99%

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Rupp

Zarain‐Herzberg

Maisch

2002

Herz

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Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.

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“…In method a, appropriate bromides were added to diethyl malonate affording diethyl monosubstituted malonate derivatives type 1, which gave the monoesters type 2 after saponification. 25 Ethyl R-substituted-acrylates 3a-e were obtained by treatment of ethyl monosubstituted malonates 2 and paraformaldehyde, under Knoevenagel reaction. Compound 3f was obtained by substitution of the acetoxy group of acrylate 4, by nucleophilic attack of the appropriate Grignard reagent, in the presence of CuI (method b).…”

Section: Chemistrymentioning

confidence: 99%

Phosphinic Pseudo-Tripeptides as Potent Inhibitors of Matrix Metalloproteinases: A Structure−Activity Study

et al. 1999

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Several phosphinic pseudo-tripeptides of general formula R-XaaPsi(PO(2)-CH(2))Xaa'-Yaa'-NH(2) were synthesized and evaluated for their in vitro activities to inhibit stromelysin-3, gelatinases A and B, membrane type-1 matrix metalloproteinase, collagenases 1 and 2, and matrilysin. With the exception of collagenase-1 and matrilysin, phosphinic pseudo-tripeptides behave as highly potent inhibitors of matrix metalloproteinases, provided they contain in P(1)' position an unusual long aryl-alkyl substituent. Study of structure-activity relationships regarding the influence of the R and Xaa' substituents in this series may contribute to the design of inhibitors able to block only a few members of the matrix metalloproteinase family.

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Synthesis and hypoglycemic activity of phenylalkyloxiranecarboxylic acid derivatives

Cited by 40 publications

References 11 publications

Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: Hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals

Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: Hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Phosphinic Pseudo-Tripeptides as Potent Inhibitors of Matrix Metalloproteinases: A Structure−Activity Study

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