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QSAR analysis of hypoglycemic agents using the topological indices.

The molecular topology model and discriminant analysis have been applied to the prediction of some pharmacological properties of hypoglycemic drugs using multiple regression equations with their statistical parameters. Regression analysis showed that the molecular topology model predicts these properties. The corresponding stability (cross-validation) studies performed on the selected prediction models confirmed the goodness of the fits. The method used for hypoglycemic activity selection was a linear discriminant analysis (LDA). We make use of the pharmacological distribution diagrams (PDDs) as a visualizing technique for the identification and selection of new hypoglycemic agents, and we tested on rats the predictive ability of the model.

Animals↗

PubMed1993

A novel series of N-(1-aminoalkylidene)carboximidamides as potential hypoglycemic agents.

Nitrogen heterocyclic carboximidamides, such as linogliride, 1a, have been shown to possess significant hypoglycemic activity and have shown clinical efficacy as potential antidiabetic agents. We evaluated the biological significance of the heterocyclic ring A of general structure 1, which has always been maintained in this class of compounds, by preparing acyclic compounds of general structure 2. Preliminary in vivo biological testing, i.e., the glucose tolerance test in rats, indicates that a number of the specific acyclic carboximidamides prepared, 6a-kk, possessed significant hypoglycemic activity often comparable to, and in some cases better than, the activity noted for our model compound, 1a. These results suggest that the heterocyclic ring A of 1 is not essential for hypoglycemic activity for this class of compounds.

Amides↗

PubMed1992

Synthesis and hypoglycemic activity of substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines.

A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines were prepared using two approaches, the condensation of alpha-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a [(beta-hydroxyalkyl)amino]pyrazine. These imidazo[1,2-a]pyrazines were evaluated for their binding affinity to the alpha 1, alpha 2, beta 1, and beta 2 adrenergic receptors as well as their ability to lower blood glucose in insulin resistant hyperglycemic ob/ob mice. Modifications on 8-(1-piperazinyl)imidazo[1,2-a]pyrazine (4) reduced alpha 2 binding, lowered hypoglycemic potency, and showed variations in binding to the alpha 1, beta 1, and beta 2 adrenergic receptors. In addition to 4, the 2-methyl, 3-methyl, and 5-methyl 8-(1-piperazinyl)imidazo[1,2-a]pyrazines (16k, 25m, and 16f, respectively) displayed high affinity for the alpha 2 receptor and were potent hypoglycemic agents when compared to 2-amino-7,8-dihydro-4-(1-piperazinyl)-6H-thiopyrano[3,2- d]pyrimidine (MTP-1403, 2). Receptor binding was modified by use of a 4-methylpiperazine moiety which reduced alpha 1 and beta 1 binding while retaining some hypoglycemic activity. The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.

Adrenergic alpha-Antagonists↗

PubMed1991

Substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones as hypoglycemic agents.

A series of dihydrobenzofuran and dihydrobenzopyran thiazolidine-2,4-diones (compounds 3-26) was synthesized from the corresponding aryl aldehydes 1 in two steps. These compounds represent conformationally restricted analogues of the novel hypoglycemic ciglitazone. The series was evaluated by hypoglycemic effects in vitro by measuring stimulation of 2-deoxyglucose uptake in L6 myocytes and stimulation of expression of the glucose transporter protein in 3T3-L1 adipocytes. In vivo hypoglycemic effects were evaluated in the genetically obese ob/ob mouse, and structure-activity relationships are discussed. On the basis of this in vivo potency, we have selected the 2(R)-benzylbenzopyran derivative to be further studied in a clinical setting.

Adipose Tissue↗

PubMed1993

Isolation of pseudoprototimosaponin AIII from rhizomes of Anemarrhena asphodeloides and its hypoglycemic activity in streptozotocin-induced diabetic mice.

A hot-H2O extract of rhizomes of Anemarrhena asphodeloides, the Japanese sino-medicine "chimo," lowered the blood glucose level in alloxan-diabetic mice. Hypoglycemic activity-guided fractionation isolated a new glycoside, pseudoprototimosaponin AIII [1], which was compared with chemically known prototimosaponin AIII [2]. These compounds exhibited hypoglycemic effects in a dose-dependent manner in streptozotocin-diabetic mice but showed no effects on glucose uptake and insulin release, suggesting that the hypoglycemic mechanism may be due to inhibition of hepatic gluconeogenesis and/or glycogenolysis.

Animals↗

PubMed1996

Hypoglycemic effect of the rhizomes of Polygala senega in normal and diabetic mice and its main component, the triterpenoid glycoside senegin-II.

The hypoglycemic effect of the rhizomes of Polygala senega L. var. latifolia Torrey et Gray (Polygalaceae) was investigated in normal and KK-Ay mice, one of the model animals of non-insulin dependent diabetes mellitus (NIDDM). The n-butanol extract of senega rhizomes (SN) (5 mg/kg) reduced the blood glucose of normal mice from 191 +/- 3 to 120 +/- 3 mg/dl 4 hours after intraperitoneal administration (P < 0.001), and also showed a significant decrease in the glucose level of KK-Ay mice from 469 +/- 38 to 244 +/- 14 mg/dl under similar conditions (P < 0.001). But streptozotocin-induced diabetic mice did not experience a change in the blood glucose after administration of SN. We propose that the hypoglycemic effect of SN occurs without altering the insulin concentration. Moreover, SN needs the presence of insulin in order to act. In addition, one of the active components of the hypoglycemic effect was identified as a triterpenoid glycoside, senegin-II.

Animals↗

PubMed1994

Bellidifolin: a potent hypoglycemic agent in streptozotocin (STZ)-induced diabetic rats from Swertia japonica.

Hypoglycemic activity-guided fractionation led to the isolation of five known xanthones and two triterpenoids from the ethyl acetate soluble fraction of Swertia japonica and their identification was based on spectroscopic methods. One of the triterpenes, thysanolactone, was first isolated from this plant. Among the xanthones, bellidifolin showed a potent and dose-dependent hypoglycemic activity in STZ-induced diabetic rats both in i.p. and p.o. administration. A comparative hypoglycemic activity of the other three xanthones together with bellidifolin was also studied.

Animals↗

PubMed1992

Hypoglycemic activity of olive leaf.

The hypoglycemic activity of olive leaf was studied. Maximum hypoglycemic activity was obtained from samples collected in the winter months, especially in February. One of the compounds responsible for this activity was oleuropeoside, which showed activity at a dose of 16 mg/kg. This compound also demonstrated antidiabetic activity in animals with alloxan-induced diabetes. The hypoglycemic activity of this compound may result from two mechanisms: (a) potentiation of glucose-induced insulin release, and (b) increased peripheral uptake of glucose.

Animals↗

PubMed1998

Insulin secretion from isolated rat islets induced by the novel hypoglycemic agent A-4166, a derivative of D-phenylalanine.

A derivative of D-phenylalanine, A-4166, reportedly evokes a more rapid and short-lived hypoglycemic action in vivo than any of the currently available sulfonylureas. This novel oral hypoglycemic agent is structurally different from sulfonylureas. Therefore, studies were designed to elucidate the mechanisms by which A-4166 stimulates insulin secretion. Insulin release from incubated or perifused rat islets was dose-dependently stimulated by 10 to 200 mumol/l A-4166, in the presence of 2.8 mmol/l glucose. Both A-4166 and tolbutamide evoke a prompt rise in insulin secretion followed by a sustained gradually decreasing release from perfused islets in the presence of low glucose, although A-4166 appeared to be more sensitive than tolbutamide to subthreshold glucose concentration. Diazoxide abolished the initial release and blunted sustained release. Removing calcium from the perifusate abolished insulin release within 15 minutes. A-4166 inhibited [3H]-glibenclamide binding to HIT cell membranes and 86Rb efflux from ATP-depleted or diazoxide-treated cells. These results suggest that the insulin release induced by A-4166 is relevant to this agent occupying the tolbutamide binding sites. Therefore, one possible mechanism accounting for the more rapid and short-lived hypoglycemic action of A-4166 in vivo, as compared with tolbutamide, may involve the reported differences in the bioavailability of A-4166.

ATP-Binding Cassette Transporters↗

PubMed2003

Hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] [Anacardiaceae] stem-bark aqueous extract in rats.

This study was undertaken to evaluate the hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae] stem-bark aqueous extract in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic Wistar rats. In one set of experiments, graded doses of S. birrea stem-bark aqueous extract (SB, 100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant aqueous extract (SB, 800 mg/kg p.o.) was used. The hypoglycemic effect of this single dose (SB, 800 mg/kg p.o.) of S. birrea stem-bark aqueous extract was compared with that of chlorpropamide (250 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate to high doses of S. birrea stem-bark extract (SB, 100-800 mg/kg p.o.) produced dose-dependent, significant reductions (P < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. Chlorpropamide (250 mg/kg p.o.) also produced significant reductions (P < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administrations of the single dose of S. birrea stem-bark aqueous extract (SB, 800 mg/kg p.o.) significantly reduced (P 0.01 < 0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that aqueous extract of Sclerocarya birrea possesses hypoglycemic activity, and thus lend credence to the suggested folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus in some African communities.

Administration, Oral↗

PubMed2003

Inhibition of endogenous glucose production accounts for hypoglycemic effect of Spergularia purpurea in streptozotocin mice.

The purpose of this study was to determine the underlying mechanism of the hypoglycemic activity of the aqueous extract perfusion of Spergularia purpurea (SP) in diabetic mice and streptozotocin-induced diabetic rats. The aqueous extract was administered intravenously and the blood glucose levels were determined within 4 hours after starting the treatment. Plasma insulin concentrations and endogenous glucose production were also determined. The aqueous extract at a dose of 10 mg/kg produced a significant decrease in blood glucose levels in normal rats (P < 0.05), and even more in diabetic rats (P < 0.001). This hypoglycemic effect might be due to an extra-pancreatic action of the aqueous extract of SP, since the basal plasma insulin concentrations were unchanged after SP treatment. In diabetic mice, a similar effect was observed and the results showed that aqueous extract of SP caused a potent inhibitor effect on basal endogenous glucose production (p < 0.001). We conclude that aqueous extract perfusion of SP inhibits endogenous glucose production in mice. This inhibition is at least one mechanism explaining the observed hypoglycemic activity of this plant in diabetic animals.

Animals↗

PubMed2001

Effect of KAD-1229, a nonsulfonylurea hypoglycemic agent, on plasma glucose and insulin in streptozotocin-induced diabetic dogs.

Hypoglycemic agents with a rapid onset and short duration of action should be useful for controlling postprandial hyperglycemia. Our aim was to establish a diabetes mellitus model in dogs, and then during an oral glucose tolerance test to compare the hypoglycemic effect and insulinotropic action of KAD-1229, a new hypoglycemic agent, with that of gliclazide, a conventional sulfonylurea. In this model, KAD-1229 reduced the increase in plasma glucose level without producing hypoglycemia. Gliclazide had a weaker effect on reduction of the glucose increase and caused hypoglycemia via a significantly raised insulin secretion in the late phase. A rapid insulinotropic action of KAD-1229 was clearly observed in the portal venous blood. The results suggest that in type 2 diabetes caused by, at least, insulin deficiency, KAD-1229 may improve impaired insulin secretion in the early phase and attenuate hyperglycemia without causing a sustained hypoglycemia.

Animals↗

PubMed2001

Effect of short-term glucose control on glycemic thresholds for epinephrine and hypoglycemic symptoms.

Hypoglycemia is the principal barrier to achieving target glucose goals in type 2 diabetes. The effect of short-term improvement in glycemic control on plasma glucose thresholds for symptomatic and hormonal responses to hypoglycemia in type 2 diabetes is not known. We hypothesized that the thresholds for these events would be increased by 1 wk of improved glycemic control in elderly patients with type 2 diabetes. Ten elderly patients with type 2 diabetes were admitted for an 8-d inpatient protocol. All subjects underwent insulin-induced hypoglycemia on days 2 (preglucose control) and 8 (postglucose control). Between days 2 and 8, subjects received intensive diabetes management to improve their glycemic control. Timed blood glucose profiles were obtained daily during the week before and during admission. Plasma glucose, counterregulatory hormones, and hypoglycemic symptoms were assessed at baseline and every 10 min during the hypoglycemic studies. Mean blood glucose concentrations were significantly reduced by intensive diabetes management from 9.8 +/- 3.7 mmol/liter to 7.7 +/- 3.3 mmol/liter (P < 0.001). The plasma glucose threshold for epinephrine release during insulin-induced hypoglycemia was significantly increased by intensive management from a glucose concentration of 3.7 +/- 0.5 mmol/liter at baseline to 3.1 +/- 0.3 mmol/liter after intensive management (P < 0.05). The plasma glucose threshold for hypoglycemic symptoms was also increased by intensive therapy from a glucose concentration of 5.3 +/- 1.2 to 3.3 +/- 0.6 mmol/liter (P = 0.003). These rapid changes may increase the risk for severe hypoglycemia in type 2 diabetes and limit the ability of physicians to rapidly correct hyperglycemia in elderly type 2 diabetes patients.

Aged↗

PubMed1995

The difference in hypoglycemic action between polygonati rhizoma and polygonati officinalis rhizoma.

The hypoglycemic effect of the rhizomes of Polygonatum sibricum and Polygonatum officinale (Liliaceae) was investigated in KK-Ay mice, one of the animal models of non-insulin dependent diabetes mellitus (NIDDM). The methanol extract of the rhizomes of both Polygonatum sibricum (OM) and Polygonatum officinale (IM) (800 mg/kg) reduced the blood glucose levels in KK-Ay mice 4h after intraperitoneal administration. In terms of hypoglycemic effect, the blood glucose of 1M was lower than that of OM. IM-treated mice significantly decreased the blood glucose level in an insulin tolerance test, but OM-treated mice did not change. We estimated that the hypoglycemic effect of IM raised insulin sensitivity.

Animals↗

PubMed1997

Effect of a new hypoglycemic agent, A-4166 [(-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine], on postprandial blood glucose excursion: comparison with voglibose and glibenclamide.

(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) is a new nonsulfonylurea hypoglycemic agent that lowers blood glucose by stimulating insulin release. In the present study, we examined the effects of A-4166, voglibose (an alpha-glucosidase inhibitor), and glibenclamide (a sulfonylurea) on the postprandial glycemic increase in rats with or without diabetes mellitus. Oral administration of A-4166 (25-100 mg/kg) dose-dependently decreased blood glucose with a rapid onset and short duration in normal rats. On the other hand, glibenclamide (1-4 mg/kg) showed a slower onset of its hypoglycemic action, and voglibose (0.2 mg/kg) had no effect. In the case of postprandial glucose excursion, the carbohydrate-induced increase in blood glucose was reduced by oral administration of either A-4166 or voglibose without causing sustained hypoglycemia in both normal and neonatal streptozotocin-induced diabetic rats. However, the efficacy of voglibose varied with the type of carbohydrate load. Glibenclamide produced a prolonged decrease in blood glucose without any appreciable effect on the initial glucose excursion. After sucrose loading, plasma insulin levels during the initial 1 h were significantly higher in A-4166-treated rats than in control rats, while voglibose completely inhibited the insulin response to sucrose. In glibenclamide-treated rats, an augmented insulin response was not seen. In conclusion, unlike other hypoglycemic agents, A-4166 suppresses postprandial glucose excursions by stimulating the early phase of insulin secretion.

Animals↗

PubMed2000

The hypoglycemic effect of (7R,9aS)-7-phenyl-octahydroquinolizin-2-one in mice.

(-)-Multiflorine (1), which was isolated from leguminous plants, produced a hypoglycemic effect when administered to mice with streptozotocin-induced diabetes. (-)-Multiflorine has an enaminone type conjugation on the A-ring, which is unusual in lupine alkaloids. Proceeding on the assumption that the A-B ring is responsible for the activity, several compounds bearing quinolizidin-2-one were synthesized and their hypoglycemic effects were examined. The hypoglycemic effect of (7R*,9aS*)-7-phenyl-octahydroquinolizin-2-one was approximately 4 times stronger than that of (-)-multiflorine measured by oral glucose tolerance test in normal mice. This result indicates that compounds possessing the quinolizidin-2-one ring system as the basic structure may be possible lead compounds for a new type of diabetes drug.

Alkaloids↗

PubMed2001

Relative hypoglycemic effect of insulin suppositories in diabetic beagle dogs: optimization of various concentrations of sodium salicylate and polyoxyethylene-9-lauryl ether.

The effect of insulin suppositories containing different amounts and concentrations of sodium salicylate (50, 100 mg) and polyoxyethylene-9-lauryl ether (POELE 1, 3, 4%), respectively, on the plasma glucose concentration of diabetic beagle dogs was investigated after rectal administration. Comparison of the effects of these formulations was made with that produced after subcutaneous insulin injections. Insulin suppositories containing sodium salicylate (50 mg) produced a maximum reduction of plasma glucose concentration (Cmax) of 55 +/- 11%, an area under the curve (AUC) of 252 +/- 59% reduction h; and a relative hypoglycemia (RH) of 49 +/- 12% relative to subcutaneous injection of insulin (4 U/kg). Increasing sodium salicylate to 100 mg/suppository did not improve the hypoglycemic effect of insulin suppositories further. Investigation of the influence of insulin suppositories containing different concentrations of the nonionic surfactant POELE (1, 3, 4%) showed that; the suppositories containing the lowest concentration (1%) produced the highest hypoglycemic effect with a Cmax of 68%, AUC of 332 +/- 67% reduction h, and RH of 55 +/- 11%. Incorporation of sodium salicylate 50mg in insulin suppositories containing 1% POELE did not improve further the effects found with these suppositories. In conclusion, a relative hypoglycemic effect of about 50-55% can be achieved using insulin suppositories containing Witepsol W35 as a base, insulin (5 U/kg), and sodium salicylate (50 mg) or POELE (1%) as rectal absorption enhancers.

Administration, Rectal↗

PubMed1993

2'-Hydroxymatteucinol, a new C-methyl flavanone derivative from Matteccia orientalis; potent hypoglycemic activity in streptozotocin (STZ)-induced diabetic rat.

The CHCl3 extract of Matteccia orientalis showed very strong hypoglycemic activity in streptozotocin (STZ)-induced diabetic rats. A new C-methyl flavanone derivative, 2'-hydroxymatteucinol (3) was isolated from the hypoglycemic activity bearing fraction, along with two known compounds, demethoxymatteucinol (1) and matteucinol (2). The structures of these isolated compounds were elucidated by spectroscopic methods. One of the compounds isolated from CHCl3 extract, 2'-hydroxymatteucinol (3), showed dose-dependent hypoglycemic activity, and a blood sugar lowering effect was observed even at the dose of 10 mg/kg (p.o.) in STZ-induced diabetic rats.

Animals↗