Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20 4401
(4) (a) Kinoshita, J . H. A Thirty Year J ourney in the Polyol Pathway.
Exp. Eye Res. 1990, 50, 567-573. (b) Kinoshita, J . H.; Nish-
imura, C. The Involvement of Aldose Reductase in Diabetic
Complications. Diabetes Metab. Rev. 1988, 4, 323-337.
(5) Mylari, B. L.; Oates, P. J .; Beebe, D. A.; Brackett, N. S.; Coutcher,
J . B.; Michael S.; Dina, M. S.; Zembrowski, W. J . Sorbitol
Dehydrogenase Inhibitors (SDIs): A New Potent, Enantiomeric
SDI, 4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sul-
fonic Acid Dimethylamide. J . Med. Chem. 2001, 44, 2695-2700.
(6) Cameron, N. E.; Cotter, M. A.; Basso, M.; Hohman, T. C.
Comparison of the Effects of Inhibitors of Aldose Reductase and
Sorbitol Dehydrogenase on Neurovascular Function, Nerve
Conduction and Tissue Polyol Pathway Metabolites in Strepto-
zotocin-Diabetic Rats. Diabetalogia 1997, 40, 271-281.
(7) Ido, Y.; Chang, K.; Oates, P. J .; Mylari, B. L.; Williamson, J . R.
Inhibitors of Sorbitol Dehydrogenase (SDI) and Aldose Reductase
(ARI) Reverse Impaired Motor Nerve Conduction Velocity
(MNCV) in Diabetic Rats. Diabetes 1999, 48 (Suppl. 1), A150.
(8) Ng, T. F.; Lee, F. K.; Song, Z. T.; Calcutt, N. A.; Lee, A. Y.;
Chung, S. S.; Chung, S. K.; Ng, D. T.; Lee, L. W. Effects of
Sorbitol Dehydrogenase Deficiency on Nerve Conduction in
Experimental Diabetic Mice. Diabetes 1998, 47, 961-966.
(9) Ballinger, W. E.; Day, W. W.; Beebe, D. A.; Oates, P. J .;
Zembrowski, W. J .; Mylari, B. L. The Effect of Multiple Bolus
Dosing vs Chronic Water Dosing with CP-166,572, a Potent
Sorbitol Dehydrogenase Inhibitor, on Nerve Fructose Normaliza-
tion in Diabetic Rats. Presented at the 7th North American ISSX
Meeting, San Diego, CA, October 20, 1996.
Ta ble 1. In Vitro and in Vivo Data of SDIs
IC50 (nM)
a
no.
rat
human
ED90, mpk
2a
9
11b
11
7
10
13
4
4
c
2
1
1
1
c
10
11a
11b
16
16a
17
21
22
24
6
32
4b
9
39
5
5
0.05
16
43
7
7
c
d
e
0.3
1
10
20
f
a
b
Chronic test, Side-by-side comparison, c Not determined,
56% at 0.05 mpk. e 81% at 1 mpk. f 65% at 1 mpk.
d
target enzyme potency/selectivity, low molecular weight,
good solubility, low protein binding, modest lipophilicity,
excellent Caco-2 Papp for good oral absorption, and
sufficiently long plasma t1/2, both in rats and dogs, to
support sustained duration of action. This compound
should allow powerful, long-acting in vivo inhibition of
SDH and allow clarification of the role of the metabolic
flux through SDH in the development of diabetic
complications.
(10) Avery, M.; Ballinger, W. E.; Zembrowski, W. J .; Inskeep, P. B.;
Mylari, B. L.; Fouda, H. G. Microbore HPLC/MS of CP-166,572
Metabolites in the Rat. Presented at the American Society Mass
Spectrometry Conference, Atlanta, GA, May 21, 1995.
(11) Chu-Moyer, M. Y.; Ballinger, W. E.; Beebe, D. A.; Berger, R.;
Coutcher, J . B.; Day, W. W.; Li, J .; Mylari, B. L.; Oates, P. J .;
Weekly, R. M. Orally-Effective, Long-Acting Sorbitol Dehydro-
genase Inhibitors: Synthesis, Structure-Activity Relationships,
and in Vivo Evaluations of Novel Heterocycle-Substituted Pip-
erazino-Pyrimidines. J . Med. Chem. 2002, 45, 511-528.
(12) Chu-Moyer, M. Y.; Ballinger, W. E.; Beebe, D. A.; Coutcher, J .
B.; Day, W. W.; Li, J .; Oates, P. J .; Weekly, R. M. SAR and
Species/Stereo-Selective Metabolism of the Sorbitol Dehydroge-
nase Inhibitor, CP-470,711. Bioorg. Med. Chem. Lett. 2002, 12,
1477-1480.
Su p p or tin g In for m a tion Ava ila ble: Description of syn-
thetic schemes and spectral data. This material is available
Refer en ces
(1) Geisen, K.; Utz, R.; Grotsch, H.; Lang, J .; Nimmesgern, H.
Sorbitol-Accumulating Pyrimidines: Arzneim. Forsch. 1994, 44,
1032-1043.
(13) Mylari et al. Unpublished observation.
(2) (a) Williamson, J . R.; Chang, K.; Frangos, M.; Hasan, K. S.; Ido,
Y.; Kawamura, T.; Nyengaard, J . R.; Van den Enden, M.; Kilo,
C.; Tilton, R. G. Hypergylcemic Pseudohypoxia and Diabetic
Complications. Diabetes. 1993, 42, 801-813. (b). Tilton, R. G.;
Chang, K.; Nyengaard, J . R.; Van den Enden, M.; Ido, Y.;
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on Vascular and Neural Dysfunction in Streptozotocin-Induced
Diabetic Rats. Diabetes 1995, 44, 234-242.
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(15) Complete experimental procedures for compounds discussed here
can be found in Patents WO 0059510 and CAN 133:281794.
(16) J effery, J .; J ornvall, H. Sorbitol Dehydrogenase. Adv. Enzymol.
1988, 61, 47-106.
(17) We thank Mr. W. E. Ballinger of Pharmacokinetics, Dynamics
& Metabolism Department within Pfizer Global Research and
Development, for this result.
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