Carbonic anhydrase inhibitors. Part 60. The topical intraocular pressure-lowering properties of metal complexes of a heterocyclic sulfonamide: influence of the metal ion upon biological activity

Metal complexes of a sulfonamide possessing strong carbonic anhydrase (CA) inhibitory properties have been obtained from the sodium salt of the sulfon amide or from the free sulfonamide in the presence of ammonia, and the foll owing metal ions: Mg(II); Zn(II); Mn(II); Cu(II); Co(II); Ni(II); Be(II); C d(II); Pb(II); Al(III); Fe(III) and La(III). The original sulfonamide, 5-(3 ,4-dichlorophenylureido)-1,3,4-thiadiazole-2-sulfonamide and its complexes were assayed for in vitro inhibition of three CA isozymes, CA I, II and IV, some of which play a critical role in ocular fluid secretion. All these co mpounds (the sulfonamide and its metal complexes) behave as very powerful i nhibitors against the three investigated CA isozymes. The parent sulfonamid e possesses strong topical pressure lowering effects in rabbits when applie d as a 1% solution directly into the eye, but some of its metal complexes, such as the Mg(II); Zn(II); Mn(II) and Cu(II) derivatives, lower intraocula r pressure (IOP) in experimental animals much better. Ex vivo data showed a 98.5-99.9% inhibition of CA II and IV in ocular fluids and tissues of the rabbits treated with these agents, proving that the IOP lowering properties are due to CA inhibition. The influence of the different metal ions upon t he efficiency of the obtained complexes as pressure lowering drugs are disc ussed, considering the possibility to design in this way more selective pha rmacological agents from this class. (C) 1999 Editions scientifiques et med icales Elsevier SAS.