Publication Details (including relevant citation information):
Journal of Medicinal Chemistry (1992), 35(3), 457-65
A broad structure-activity program was undertaken in search of effective
surrogates for the key benzothiazole side chain of the potent aldose
reductase inhibitor, zopolrestat. A structure-driven approach was
pursued, which spanned exploration of three areas: (1) 5/6 fused
heterocycles, such as benzoxazole, benzothiophene, benzofuran, and
imidazopyridine; (2) 5-membered heterocycles, including oxadiazole,
oxazole, thiazole, and thiadiazole, with pendant aryl groups, and (3)
thioanilide as a formal equiv. of benzothiazole. Several benzoxazole- and
1,2,4-oxadiazole-derived analogs were found to be potent inhibitors of
aldose reductase from human placenta and were orally active in preventing
sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic
complications. Phthalazineacetic acid I was the best of the benzoxazole
series ([C50 = 3.2 .times. 10-9M); it suppressed accumulation of sorbitol
in rat sciatic nerve by 78% at an oral dose of 10 mg/kg. Oxadiazolyl
deriv. II with IC50 < 1.0 .times. 10-8M, caused a 69% redn. in sorbitol
accumulation in rat sciatic nerve at an oral dose of 25 mg/kg. The
thioanilide side chain features in III proved to be an effective surrogate
for benzothiazole. III was highly potent in vitro (IC50 = 5.2 .times.
10-8M) but did not show oral activity when tested at 100 mg/kg. Addnl.
structure-activity relationships encompassing a variety of heterocyclic
side chains are discussed.
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