Pamela Scott - Potent, orally active aldose reductase inhibitors related to zopolrestat:

Version 1

      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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