Potent inhibition of glycogen phosphorylase by a spirohydantoin of glucopyranose: First pyranose analogues of hydantocidin

Bichard, C. J. F.; Mitchell, Edward P.; Wormald, Mark R.; Watson, Kimberly A.; Johnson, L.N.; Zographos, S.E.; Koutra, D. D.; Oikonomakos, Nikos G.; Fleet, George W. J.

doi:10.1016/0040-4039(95)00197-k

Cited by 144 publications

(106 citation statements)

References 13 publications

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“…2). CP-91149 is structurally distinct from previously described glucose or I-site inhibitors (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), and is, in direct comparison with caffeine, 200-fold more potent. Despite the structural differences between CP-91149 and caffeine, we observed the same glucose synergy by these agents; HLGPa inhibition by both compounds increased 5-to 10-fold over a 0-10 mM glucose concentration range (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…Glucose production from the catalysis of glycogen to glucose-1-phosphate is rate-limited by phosphorylase a, a well-studied enzyme that is regulated by multiple covalent, substrate, and allosteric effectors (12). To date, two types of glycogen phosphorylase inhibitors have been reported: glucose analogs bearing multiple polar functionalities, which bind near the active site of the enzyme (13)(14)(15)(16)(17)(18), and caffeine and other heteroaromatic analogs, which bind at the purine inhibitory site, also known as the I-site (19)(20)(21)(22). Although some glucose and purine nucleoside phosphorylase inhibitors reportedly inhibit glycogenolysis in rodent cells and tissues (22)(23)(24), none of these are known to be orally active in vivo, possibly because of inadequate potency or poor pharmacokinetics, limiting their utility in determining the effect of glycogenolysis inhibition on HGP.…”

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confidence: 99%

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Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo

Martin

Hoover²,

Armento³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

227

209

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An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*,S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC 50 of 0.13 M in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5-to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 M) and in primary human hepatocytes (2.1 M IC 50 ). In vivo, oral administration of CP-91149 to diabetic ob͞ob mice at 25-50 mg͞kg resulted in rapid (3 h) glucose lowering by 100-120 mg͞dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob͞ob mice pretreated with 14 C-glucose to label liver glycogen, CP-91149 administration reduced 14 C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic f lux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo

Martin

Hoover²,

Armento³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

227

209

View full text Add to dashboard Cite

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“…2a for an illustration). The synthetic problems with the stereoselective preparation of the properly configured spiro-hydantion 8 [17][18][19] were essentially overcome by the highly stereoselective synthesis of spiro-thiohydantoin 10 [20] which proved equipotent with 8 ( Fig. 3).…”

Section: Early Glucose Analogue Inhibitors Of Glycogen Phosphorylasementioning

confidence: 99%

Glucose derived inhibitors of glycogen phosphorylase

Somsák

2010

Comptes Rendus. Chimie

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“…Its intriguing structure and remarkable biological properties have stimulated a considerable amount of synthetic work on the parent compound (9)(10)(11)(12)(13)(14) and its analogues (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The novel injury symptoms it elicits in plants has prompted a detailed investigation of its mode of action.…”

mentioning

confidence: 99%

The mode of action and the structure of a herbicide in complex with its target: binding of activated hydantocidin to the feedback regulation site of adenylosuccinate synthetase.

Fonné‐Pfister

Chemla

Ward

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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(+)-Hydantocidin, a recently discovered natural spironucleoside with potent herbicidal activity, is shown to be a proherbicide that, after phosphorylation at the 5' position, inhibits adenylosuccinate synthetase, an enzyme involved in de novo purine synthesis. The mode of binding of hydantocidin 5'-monophosphate to the target enzyme was analyzed by determining the crystal structure of the enzyme-inhibitor complex at 2.6-A resolution. It was found that adenylosuccinate synthetase binds the phosphorylated compound in the same fashion as it does adenosine 5'-monophosphate, the natural feedback regulator of this enzyme. This work provides the first crystal structure of a herbicide-target complex reported to date.

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Potent inhibition of glycogen phosphorylase by a spirohydantoin of glucopyranose: First pyranose analogues of hydantocidin

Cited by 144 publications

References 13 publications

Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo

Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo

Glucose derived inhibitors of glycogen phosphorylase

The mode of action and the structure of a herbicide in complex with its target: binding of activated hydantocidin to the feedback regulation site of adenylosuccinate synthetase.

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