New Potent α-Glucohydrolase Inhibitor MDL 73945 With Long Duration of Action in Rats

Robinson, Keith; Begovic, Mary E.; Rhinehart, Barry L.; Heineke, Eric W; Ducep, Jean‐Bernard; Kastner, Philip R.; Marshall, Franklin N.; Danzin, Charles

doi:10.2337/diab.40.7.825

Cited by 80 publications

(29 citation statements)

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“…No Kj va lues were determined, the figures cited being relative values for the inhibitory effect in comparison to acarbose. These data differ in a few cases from so me results in the literature, which are also not always consistent (LEMBCKE et al 1985;SCOFIELD et al 1986;SAMULITIS et al 1987;YOSHIKUNI et al 1988;ROBINSON et al 1991ROBINSON et al , 1992. This is partly due to the fact that the disaccharidases used are not pure enzymes and originated from the sm all intestines of various mammalian sources (pig, rabbit, rat, mouse).…”

Section: -Deoxynojirimycincontrasting

confidence: 56%

“…Pharmacokinetic parameters, especially absorption from the gastrointestinal tract, enterohepatic circulation, rate of enzyme synthesis, etc., all play a (ROBINSON et al 1991). In contrast the 1-deoxynojirimycin derivative 93 (emiglitate) is still active if it is administered 17 h before the sucrose loading, possibly because it is recycled to the intestinal enzymes via the enterohepatic circulation.…”

Section: -Deoxynojirimycinmentioning

confidence: 99%

“…a Relative sucrase inhibitory activity: SIU /mg test compound/SIU /mg acarbose . °Data from SCHMIDT et al (1979), SCOFIELO et al (1986), YOSHIKUNI (1988), YOSHIKUNI et al (1988), ROBINSON et al (1991ROBINSON et al ( , 1992 containing a double bond in the allyl position (116,118,119). Derivatives with a tripie bond, however, have a weaker relative effect (117).…”

Section: -Deoxynojirimycinmentioning

confidence: 99%

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Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Junge¹,

Matzke²,

Stoltefuß³

1996

Oral Antidiabetics

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A. IntroductionWhen intestinal sucrase and pancreatic a-amylase were identified at Bayer as new targets for improved diabetes therapy (PULS et al. 1973), the problem remained of the best way to find a potent and selective inhibitor of these enzymes. The medicinal chemist today has two alternatives in the search for a first lead compound, firstly the screening of thousands of compounds with maximum structural diversity in a random screening approach, or secondly the rational design of a lead compound, when the biochemical mechanism and the structure of the enzyme are weIl known. In the late 1960s, when we started to look for such potent and selective inhibitors, we had to choose the random screening approach, relying mainly on testing of extracts of the culture broths of microorganisms.Today the mechanism of enzymatic splitting of sucrose by intestinal sucrase is fairly weIl understood. First the glucosidic oxygen atom of sucrose is protonated via a carboxyl group of the enzyme. The splitting of the glucosidic C-O bond is further facilitated by the glucosyl cation being stabilized by a second carboxylate group of the enzyme (COGOLI and SEMENZA 1975). FinaIly, the glucosyl cation reacts with water to give the products 0-glucose and o-fructose. The protonated sucrose molecule land the glucosyl cation 11 are two high-energy intermediates of the enzymatic reaction. Today we know that mimics of such high-energy intermediates are often potent inhibitors of the enzyme. Accordingly, compounds similar in structure to o-glucose but with an easily protonated basic N-atom either in the position of the anomeric oxygen atom (inhibitor type I) or in the position of the ring oxygen atom (inhibitor type 11) should be potent inhibitors of sucrase (Fig. 1). Interestingly, both types of inhibitors represented by either acarbose or I-deoxynojirimycin were found in our random screening. In the foIlowing sections these two types of inhibitors are not discussed in a historical order but under structural criteria. Not included in this discussion are the a-amylase inhibitors of protein nature because there is no evidence that they will find any therapeutic application.

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Section: -Deoxynojirimycincontrasting

confidence: 56%

Section: -Deoxynojirimycinmentioning

confidence: 99%

Section: -Deoxynojirimycinmentioning

confidence: 99%

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Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Junge¹,

Matzke²,

Stoltefuß³

1996

Oral Antidiabetics

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“…Successful results were first obtained with miglitol and emiglitate. The ED 50 was evaluated respectively as 0.24 and 0.16 mg/kg body weight [12,13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Activity of Novel Deoxynojirimycin Derivatives as Potent α-Glucosidase Inhibitors

2013

Zeitschrift Für Naturforschung B

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Thirteen 1-deoxynojirimycin (DNJ) derivatives of five different skeletal structures were designed and synthesized. The newly synthesized compounds were evaluated using an in vitro α-glucosidase assay, and kinetic parameters (Ki, IC 50 ) were measured. Some DNJ derivatives showed weak α-glucosidase inhibitory activities, and the compounds 1-(3-benzyloxy-2-hydroxypropyl)-2-hydroxymethyl-piperidine-3,4,5-triol (2a) and 1-{3-[1-(4-fluorophenyl)-1H-[1,2,3]triazol-4-ylmethoxy]-2-hydroxypropyl}-2-hydroxymethyl-piperidine-3,4,5-triol (13d) showed activities comparable to that of DNJ. While 2a was found to be a reversible, non-competitive inhibitor of α-glucosidase with a Ki value of 1.56 × 10 −4 M and an IC 50 value of 3.07 × 10 −4 M, 13d was a reversible, competitive inhibitor of α-glucosidase with a Ki value of 2.08 × 10 −4 M and an IC 50 value of 3.31 × 10 −4 M.

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“…Of the two popular glucosidases, α-glucosidase (EC 3.2.1.20) has drawn a special interest of the pharmaceutical research community because it was shown in earlier studies that the inhibition of its catalytic activity resulted in the retardation of glucose absorption and the decrease in postprandial blood glucose level. [3][4][5] Therefore, effective α-glucosidase inhibitors may serve as chemotherapeutic agents for clinic use in the treatment of diabetes and obesity. Due to the catalytic role in digesting carbohydrate substrates, α-glucosidase has also been well appreciated as a therapeutic target for the other carbohydrate mediated diseases including cancer, 6 viral infections, 7,8 and hepatitis.…”

Section: Introductionmentioning

confidence: 99%

Toward the Virtual Screening of α-Glucosidase Inhibitors with the Homology-Modeled Protein Structure

2008

Bulletin of the Korean Chemical Society

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Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and the other carbohydrate mediated diseases. As a method for the discovery of new novel inhibitors of α-glucosidase, we have addressed the performance of the computer-aided drug design protocol involving the homology modeling of α-glucosidase and the structure-based virtual screening with the two docking tools: FlexX and the automated and improved AutoDock implementing the effects of ligand solvation in the scoring function. The homology modeling of α-glucosidase from baker's yeast provides a high-quality 3-D structure enabling the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands to the extent of 5-fold enhancement of hit rate in database screening when 1% of database coverage is used as a cutoff. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of α-glucosidase through the simultaneous establishment of the multiple hydrogen bond and hydrophobic interactions. The present study demonstrates the usefulness of the automated AutoDock program with the improved scoring function as a docking tool for virtual screening of new α-glucosidase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors.

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New Potent α-Glucohydrolase Inhibitor MDL 73945 With Long Duration of Action in Rats

Cited by 80 publications

References 0 publications

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Synthesis and Biological Activity of Novel Deoxynojirimycin Derivatives as Potent α-Glucosidase Inhibitors

Toward the Virtual Screening of α-Glucosidase Inhibitors with the Homology-Modeled Protein Structure

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