European Journal of Pharmaceutical Sciences 2000-03-01

Carbonic anhydrase activators. Part 24. High affinity isozymes I, II and IV activators, derivatives of 4-(4-chlorophenylsulfonylureido-amino acyl)ethyl-1H-imidazole.

A Scozzafava, C T Supuran

Index: Eur. J. Pharm. Sci. 10(1) , 29-41, (2000)

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Abstract

N-1-Tritylsulfenyl histamine was synthesized by reaction of histamine (Hst) with tetrabromophthalic anhydride followed by protection of its imidazole moiety with tritylsulfenyl chloride. After hydrazinolysis, it afforded a key intermediate which was derivatized at the aminoethyl group in order to obtain new types of activators of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Reaction of the key intermediate with 4-chlorophenylsulfonylureido amino acids (cpu-AA) in the presence of carbodiimides afforded, after deprotection of the imidazolic nitrogen atom, a series of compounds with the general formula cpu-AA-Hst (cpu, 4-ClC(6)H(4)SO(2)NHCO). Some structurally related dipeptide derivatives with the general formula cpu-AA1-AA2-Hst (AA, AA1 and AA2 represent amino acyl moieties) were also prepared by a strategy similar to that applied for the amino acyl compounds mentioned above. The new derivatives proved to be efficient activators of three CA isozymes. Best activity was detected against hCA I and bCA IV, for which some of the new compounds showed affinities in the 1-10 nM range (h, human; b, bovine isozymes). hCA II, on the other hand, was less prone to activation by the new derivatives, which possessed affinities around 20-50 nM for this isozyme. This new class of CA activators might lead to the development of drugs/diagnostic agents for CA deficiency syndrome, a genetic disease of bone, brain and kidneys.