2286 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Letters
(7) Ho, E. C. M.; Lam, K. S. L.; Chung, S. S. M.; Chung, S. K. Aldose
Reductase Deficient Mice Are Alleviated from the Depletion of
GSH in the Peripheral Nerve and MNCV Deficit Associated with
Diabetes. Diabetes 2001, 50 (Suppl. 2), A59.
(8) (a) Demaine, A.; Cross, D.; Millward, A. Polymorphism of the
Aldose Reductase Gene and Susceptibility to Retinopathy in
Type I Daibetes Mellitus. Invest. Ophthalmol. Visual Sci. 2000,
41, 4064-4068. (b) Heesom, A. E.; Millward, A.; Demaine, A.
G. Susceptibility to Diabetic Neuropathy in Patients with Insulin
Dependent Diabetes Mellitus Is Associated with a Polymorphism
at the 5′ End of the Aldose Reductase Gene. J . Neurol.,
Neurosurg. Psychiatry 1998, 64, 213-216.
(9) Takahayashi, N. J . Pharm. Soc. J pn. 1956, 76, 1293-1296.
(10) Dvornik, D. A Perspective of Aldose Reductase Inhibitors and
Diabetic Complications. Croat. Chem. Acta 1996, 69, 613-630.
(11) Experimental procedures for phenyl substituted compounds can
be found in Patents EP 1236720 and CAN 137:216953.
(12) Stribling, D.; Mirrlees, D. J .; Harrison, H. E.; Earl, D. C.
Properties of ICI 128,436, a Novel Aldose Reductase Inhibitor,
and Its Effects on Diabetic Complications in the Rat. Metabolism
1985, 34 (4), 336-344.
(13) (a) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zembrowski, W.
J .; Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Singleton. D. H.
Novel, Potent Aldose Reductase Inhibitors: 3,4-Dihydro-4-oxo-
3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineace-
tic Acid (Zopolrestat) and Congeners. J . Med. Chem. 1991, 34,
108-122. (b) Mylari, B. L.; Beyer, T. A.; Scott, P. J .; Aldinger,
C. E.; Dee, M. F.; Siegel, T. W.; Zembrowski, W. J . Potent, Orally
Active Aldose Reductase Inhibitors Related to Zopolrestat:
Surrogates for Benzothiazole Side Chain. J . Med. Chem. 1992,
35, 457-465.
nism, and pharmacokinetics in rats led to the title
compound 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-
2H-pyridazin-3-one, 24. It is a novel, highly selective
ARI with unprecedented in vitro potency (840 ( 40 pM)
and remarkable potency in the sciatic nerve as well as
in the lens of chronically diabetic rats, in normalizing
polyol metabolites. It is well absorbed in diabetic rats
with a sustained plasma t1/2 of 26 ( 3 h.
Su p p or tin g In for m a tion Ava ila ble: Biological methods
and NMR and elemental analysis data. This material is
Refer en ces
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(2) (a) Tilton, R. G.; Chang, K.; Nyengaard, J . R.; Van den Enden,
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(3) Cameron, N. E.; Cotter, M. A.; Basso, M.; Hohman, T. C.
Comparison of the Effects of Inhibitors of Aldose Reductase and
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zotocin-Diabetic Rats. Diabetalogia 1997, 40, 271-281.
(4) Ao, S.; Shingu, Y.; Kikuchi, C.; Takano, Y.; Nomura, K.;
Fujiwara, T.; Ohkubo, Y.; Notsu, Y.; Yamaguchi, I. Character-
ization of a Novel Aldose Reductase Inhibitor, FR74366, and Its
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(5) Eggler, J . F.; Larson, E. R.; Lipinski, C. A.; Mylari, B L.; Urban,
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(6) (a) Malamas, M. S.; Hohman, T. C.; Millen, J . Novel Spirosuc-
cinimide Aldose Reductase Inhibitors Derived from Isoquinoline-
1,3-diones: 2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluorospiro-
[isoquinoline-4(11H),3′-pyrrolidine]-1,2′,3,5′(2H)-tetrone and
Congeners. 1. J . Med. Chem. 1994, 37, 2043-2058. (b) Hohman,
T. C.; Bochenek, W. J .; Meng, X.; Neefe, L.; Beg, M.; Ari, D. T.
Nerve Function and Biochemistry in Diabetic Patients Treated
with ARI-509, a Novel Aldose Reductase Inhibitor. Diabetologia
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(14) Wilson, D. K.; Tarle, I.; Petrash, J . M. Quiocho, F. A. Refined
1.8 Å Structure of Human Aldose Reductase Complexed with
the Potent Inhibitor Zopolrestat. Proc. Natl. Acad. Sci. U.S.A.
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(15) Kato, K.; Nakayama, K.; Mizota, M.; Miwa, I.; Okuda, J .
Properties of Novel Aldose Reductase Inhibitors, M16209 and
M16287, in Comparison with Known Inhibitors. ONO-2235 and
Sorbinil. Chem. Pharm. Bull. (Tokyo) 1991, 39, 540-545.
(16) Experimental procedures for heterocyclic substituted pyridazi-
nones can be found in Patents U.S. 2,002,143,017 and CAN 137:
279206.
(17) Indole analogue 20 was more conveniently prepared starting
from 2-mercaptoindole and following Scheme 1.
(18) Robertson, M. J .; Barnes, J . C.; Drew, G. M.; Clark, K. L.;
Marshall, F. H.; Michel, A.; Middlemiss, D.; Ross, B. C.; Scopes,
D.; Dowle, M. D. Pharmacological Profile of GR117289 in Vitro:
A Novel, Potent and Specific Non-Peptide Angiotensin AT1
Receptor Antagonist. Br. J . Pharmacol. 1992, 107, 1173-1180.
J M034065Z