Glucose Analog Inhibitors of Glycogen Phosphorylases as Potential Antidiabetic Agents: Recent Developments

Abstract

Diabetes is among the largest contributors to global mortality through its long term complications. The worldwide epidemic of type 2 diabetes has been stimulating the quest for new concepts and targets for the treatment of this incurable disease. A new target is glycogen phosphorylase (GP), the main regulatory enzyme in the liver responsible for the control of blood glucose levels. One of several approaches to influence the action of GP is the use of glucose derivatives as active site inhibitors. This field of research commenced 10-15 years ago and, due to joint efforts in computer aided molecular design, organic synthesis, protein crystallography, and biological assays, resulted in glucopyranosylidene-spiro-hydantoin 16 (K(i) = 3-4 micro M) as the most efficient glucose analog inhibitor of GP of that time. The present paper surveys the recent developments of this field achieved mainly in the last five years: the synthesis and evaluation of glucopyranosylidene-spiro-thiohydantoin 18 (K(i) = 5 micro M) which has proven equipotent with 16, and is available in gram amounts; furanosylidene- and xylopyranosylidene-spiro-(thio)hydantoins whose ineffectiveness (K(i) > 10 mM) confirmed the high specificity of the catalytic site of GP towards the D-glucopyranosyl unit; "open" hydantoins like methyl N-(1-carboxamido-D-glucopyranosyl)carbamate 37 (K(i) = 16 micro M) and N-acyl-N'-(beta-D-glucopyranosyl)ureas among them the to date best glucose analog inhibitor N-(2-naphthoyl)-N'-(beta-D-glucopyranosyl)urea (35, K(i) = 0.4 micro M) which can also bind to the so-called new allosteric site of GP; C-(beta-D-glucopyranosyl)heterocycles (tetrazole, 1,3,4-oxadiazoles, benzimidazole (K(i) = 11 micro M), and benzothiazole). Iminosugars like isofagomine (45, IC(50) = 0.7 micro M), noeuromycin (53, IC(50) = 4 micro M), and azafagomine (54, IC(50) = 13.5 micro M) also bind strongly to the active site of GP, however, substitution on the nitrogens makes the binding weaker. The natural product five-membered iminosugar DAB (56) exhibited IC(50) approximately 0.4-0.5 micro M. Azoloperhydropyridines which can be regarded iminosugar-annelated heterocycles show moderate inhibition of GP: nojiritetrazole 12 (K(i) = 53 micro M) is the best inhibitor and fewer nitrogens in the five-membered ring weakens the binding. Physiological investigations have been carried out with N-acetyl-beta-D-glucopyranosylamine 6, spiro-thiohydantoin 18, isofagomine 45, and DAB 56 to underline the potential use of these compounds in the treatment of type 2 diabetes. Computational methods suggest to synthesize further anomerically bifunctional glucose derivatives which may be good inhibitors of GP.

Carbohydrate Derivatives and Glycomimetic Compounds in Established and Investigational Therapies of Type 2 Diabetes Mellitus

“…Some glucose analogues can also occupy the new allosteric site , and the benzimidazole-site was evidenced by a 2-(-Dglucopyranosyl)-benzimidazole (Chrysina et al, 2005). The studied O-, and S-glucopyranosides proved very weak inhibitors with K i values in the 2000-25000 M and 650-21100 M, respectively (Somsák et al, 2003;Somsák et al, 2005). Extensive investigation of N-glucopyranosylamide type compounds (Table 8, Entries 1-4) revealed that a) the NHCONHCO linker between the sugar and the aromatic part of the compounds and b) a large hydrophobic substituent (compare columns B and C) make the best inhibitor (Entry 3C), actually the first glucose analogue in the nanomolar inhibition range.…”

“…A large variety of glucose based compounds were synthesized and tested mainly against the prototype of the GP enzymes, the best available rabbit muscle GP (Chrysina, 2010). For the inhibitory glucose derivatives (Gimisis, 2010;Praly & Vidal, 2010;Somsák, 2011;Somsák et al, 2003;Somsák et al, 2005) protein crystallography showed primary binding to the catalytic site of the enzyme. Some glucose analogues can also occupy the new allosteric site , and the benzimidazole-site was evidenced by a 2-(-Dglucopyranosyl)-benzimidazole (Chrysina et al, 2005).…”

“…Enlarging the heterocyclic ring to a seven-membered one (Entry 13) gave a weaker inhibitor in comparison to the six-membered pyrimidine derivatives. (Somsák et al, 2003) 1. Table 10.…”

Crataegus pinnatifida: Chemical Constituents, Pharmacology, and Potential Applications

“…A new identified compound, shanyenoside (A) (89), was isolated from the leaves of C. pinnatifida in 2006 [40]. In 2009, (88) was isolated from the leaves of C. pinnatifida [39]. Later, (7S,8R)- (96) were also isolated from the leaves of C. pinnatifida in 2010 [36].…”

“…Glycogenolysis is catalyzed in liver, muscle and brain by tissue specific isoforms of glycogen phosphorylase (GP). Because of its central role in glycogen metabolism, GP had been exploited as a model for structure assisted design of potent inhibitors, which might be relevant to the control of blood glucose concentrations in type II diabetes [87,88]. Maslinic acid isolated from C. pinnatifida was found to inhibit GP in moderate strength; the IC50 was 28 µmol/L.…”