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Chemical Compound Review

Prodiax     2-[3-[(4-bromo-2-fluoro- phenyl)methyl]-4...

Synonyms: statil, PONALRESTAT, Ponalrestatum, Tocris-0847, CHEMBL7679, ...
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Disease relevance of PONALRESTAT


Psychiatry related information on PONALRESTAT


High impact information on PONALRESTAT

  • Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat [1].
  • Ponalrestat treatment completely prevented the characteristic nerve conduction slowing and structural abnormalities of the node of Ranvier for 4 mo despite only partial preservation of axonal integrity [1].
  • Ponalrestat had no significant effect on a range of standard cardiovascular autonomic nerve function tests [2].
  • The glomerular filtration rate (clearance of [125I]iothalamate) was significantly reduced from 140 +/- 18 to 129 +/- 10 ml.min-1.1.73 m-2, 2P = 0.02) in the ponalrestat-treated patients, whereas no change was seen after placebo (142 +/- 12 vs. 141 +/- 12 ml.min-1.1.73 m-2) [5].
  • Posterior tibial nerve conduction velocity changed from 35.3 +/- 4.9 m/s at baseline to 33.4 +/- 4.0 m/s at 24 wk (NS) with placebo compared with 37.6 +/- 5.6 vs. 37.2 +/- 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 +/- 6.1 vs. 36.2 +/- 6.8 m/s (NS) with 600 mg ponalrestat [3].

Biological context of PONALRESTAT

  • The preventive effect of the aldose reductase inhibitor (ARI) ponalrestat on heart-rate variability and the development of autonomic neuropathy in the vagus nerve was investigated in the spontaneously diabetic BB rat [6].
  • The presence of ponalrestat, an AR inhibitor, significantly accelerated H2O2-induced cell death [7].
  • Optimization of these new series of spirosuccinimides through structure-activity relationship (SAR) studies, including analogy from other drug series (ponalrestat, zopolrestat), led to the design of the clinical candidate 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H ),3'- pyrrolidine]-1,2',3,5'(2H)-tetrone (41) [8].
  • Lack of competition and the structural dissimilarity of substrates and inhibitor make it unlikely that ponalrestat will utilize substrate binding sites on other enzymes, and so produce undesirable side-effects via such a mechanism [9].
  • The results, however, call into question the relationship between impaired ODC induction and diabetes-induced defects in nerve regeneration, which are insensitive to ponalrestat [10].

Anatomical context of PONALRESTAT


Associations of PONALRESTAT with other chemical compounds


Gene context of PONALRESTAT

  • Ponalrestat: a potent and specific inhibitor of aldose reductase [9].
  • The values of Ki and Kies (apparent dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for the interactions of ponalrestat with ALR1 and ALR2 has been calculated by non-linear fitting of kinetic data [9].
  • In this paper, we present a detailed mechanism for inhibition of bovine lens ALR2 by ponalrestat [9].
  • Inhibitors were administered in the diet with the diet containing 0.06% (w/w) of the sorbitol dehydrogenase inhibitors or Ponalrestat, and 0.0125% (w/w) of AL 1576 [19].
  • Generally, the similarity of effect of ponalrestat and insulin on VIP and galanin expression in this study supports a primary effect of insulin via glycaemic control [20].

Analytical, diagnostic and therapeutic context of PONALRESTAT

  • Measurement of nutritive endoneurial blood flow by microelectrode polarography and hydrogen clearance showed 44% and 45% deficits for 1 and 2 months untreated diabetes (p < 0.001) that were prevented by ponalrestat and ZD5522 treatments, respectively [21].
  • Two doses of ponalrestat were employed, 8 mg kg-1 day-1 (which is equivalent to, or greater than, the blockade employed in clinical trials), and 100 mg kg-1 day-1 [22].
  • Despite the near-normal induction of ODC activity by nerve crush in the ponalrestat-treated diabetic animals, absolute ODC activity remained lower than that in ganglia of uncrushed nerves from non-diabetics [10].
  • Patients were investigated at the beginning and the end of the run-in period (a 1-month placebo period) of a multicentre trial of an aldose-reductase inhibitor (Ponalrestat) [23].
  • RESEARCH DESIGN AND METHODS: Thirty Type 1 diabetic patients (age: 34.4 +/- 3.1 yrs; diabetes duration 13.1 +/- 1.3 yrs) were treated with 600 mg of Ponalrestat per day for 3 months using a randomized double blind placebo controlled crossover design [24].


  1. Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat. Sima, A.A., Prashar, A., Zhang, W.X., Chakrabarti, S., Greene, D.A. J. Clin. Invest. (1990) [Pubmed]
  2. Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus. Boland, O.M., Blackwell, C.C., Clarke, B.F., Ewing, D.J. Diabetes (1993) [Pubmed]
  3. Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy. Florkowski, C.M., Rowe, B.R., Nightingale, S., Harvey, T.C., Barnett, A.H. Diabetes (1991) [Pubmed]
  4. Activation of lipoprotein lipase and inhibition of B16 melanoma-induced cachexia in mice by ponalrestat, an aldose reductase inhibitor. Kawamura, I., Yamamoto, N., Sakai, F., Yamazaki, H., Naoe, Y., Inami, M., Manda, T., Shimomura, K. Anticancer Res. (1999) [Pubmed]
  5. Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 mo of aldose reductase inhibition. Pedersen, M.M., Christiansen, J.S., Mogensen, C.E. Diabetes (1991) [Pubmed]
  6. Diabetic autonomic neuropathy in BB rats and effect of ARI treatment on heart-rate variability and vagus nerve structure. Zhang, W.X., Chakrabarti, S., Greene, D.A., Sima, A.A. Diabetes (1990) [Pubmed]
  7. EGF receptor-ERK pathway is the major signaling pathway that mediates upregulation of aldose reductase expression under oxidative stress. Nishinaka, T., Yabe-Nishimura, C. Free Radic. Biol. Med. (2001) [Pubmed]
  8. Novel spirosuccinimide aldose reductase inhibitors derived from isoquinoline-1,3-diones: 2-[(4-bromo-2-fluorophenyl)methyl]-6- fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone and congeners. 1. Malamas, M.S., Hohman, T.C., Millen, J. J. Med. Chem. (1994) [Pubmed]
  9. Ponalrestat: a potent and specific inhibitor of aldose reductase. Ward, W.H., Sennitt, C.M., Ross, H., Dingle, A., Timms, D., Mirrlees, D.J., Tuffin, D.P. Biochem. Pharmacol. (1990) [Pubmed]
  10. Impaired induction of nerve ornithine decarboxylase activity in the streptozotocin-diabetic rat is prevented by the aldose reductase inhibitor ponalrestat. Pekiner, C., McLean, W.G. Br. J. Pharmacol. (1990) [Pubmed]
  11. Effects of diabetes on cholinergic transmission in two rat gut preparations. Lucas, P.D., Sardar, A.M. Gastroenterology (1991) [Pubmed]
  12. Effect of aldose reductase inhibition and insulin treatment on retinal capillary basement membrane thickening in BB rats. Chakrabarti, S., Sima, A.A. Diabetes (1989) [Pubmed]
  13. Effects of long-term aldose reductase inhibition on development of experimental diabetic neuropathy. Ultrastructural and morphometric studies of sural nerve in streptozocin-induced diabetic rats. Yagihashi, S., Kamijo, M., Ido, Y., Mirrlees, D.J. Diabetes (1990) [Pubmed]
  14. Identification and characterization of aldose reductase in cultured rat mesangial cells. Kikkawa, R., Umemura, K., Haneda, M., Kajiwara, N., Maeda, S., Nishimura, C., Shigeta, Y. Diabetes (1992) [Pubmed]
  15. Aldose reductase inhibition increases CNTF-like bioactivity and protein in sciatic nerves from galactose-fed and normal rats. Mizisin, A.P., Calcutt, N.A., DiStefano, P.S., Acheson, A., Longo, F.M. Diabetes (1997) [Pubmed]
  16. Adenosine triphosphatase in nerves and ganglia of rats with streptozotocin-induced diabetes or galactosaemia; effects of aldose reductase inhibition. Lambourne, J.E., Brown, A.M., Calcutt, N., Tomlinson, D.R., Willars, G.B. Diabetologia (1988) [Pubmed]
  17. The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat. Soulis-Liparota, T., Cooper, M.E., Dunlop, M., Jerums, G. Diabetologia (1995) [Pubmed]
  18. Diabetes-induced changes in cardiac beta-adrenoceptor responsiveness: effects of aldose reductase inhibition with ponalrestat. Austin, C.E., Chess-Williams, R. Br. J. Pharmacol. (1991) [Pubmed]
  19. Effect of sorbitol dehydrogenase inhibition on sugar cataract formation in galactose-fed and diabetic rats. Kador, P.F., Inoue, J., Secchi, E.F., Lizak, M.J., Rodriguez, L., Mori, K., Greentree, W., Blessing, K., Lackner, P.A., Sato, S. Exp. Eye Res. (1998) [Pubmed]
  20. Enteric neuropeptides in streptozotocin-diabetic rats; effects of insulin and aldose reductase inhibition. Belai, A., Calcutt, N.A., Carrington, A.L., Diemel, L.T., Tomlinson, D.R., Burnstock, G. J. Auton. Nerv. Syst. (1996) [Pubmed]
  21. Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism. Cameron, N.E., Cotter, M.A., Dines, K.C., Maxfield, E.K., Carey, F., Mirrlees, D.J. Diabetologia (1994) [Pubmed]
  22. Dissociation between biochemical and functional effects of the aldose reductase inhibitor, ponalrestat, on peripheral nerve in diabetic rats. Cameron, N.E., Cotter, M.A. Br. J. Pharmacol. (1992) [Pubmed]
  23. Reproducibility of parameters for assessment of diabetic neuropathy. The French Group for Research and Study of Diabetic Neuropathy. Valensi, P., Attali, J.R., Gagant, S. Diabet. Med. (1993) [Pubmed]
  24. Short term effect of an aldose reductase inhibitor on urinary albumin excretion rate (UAER) and glomerular filtration rate (GFR) in type 1 diabetic patients with incipient nephropathy. Ranganathan, S., Krempf, M., Feraille, E., Charbonnel, B. Diabète & métabolisme. (1993) [Pubmed]
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