TRIAZOLINONE BIPHENYLSULFONAMIDE DERIVATIVES AS ORALLY-ACTIVE ANGIOTENSIN-II ANTAGONISTS WITH POTENT AT(1) RECEPTOR AFFINITY AND ENHANCED AT(2) AFFINITY

Several series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones with acidic sulfonamide replacements of tetrazole at the 2'-position of the biphenyl-4-ylmethyl side chain at N-4 were prepared and tested as angiotensin II (AII) antagonists. Preferred substituents on the triazolinone ring were n-butyl at C-5 and 2-(trifluoromethyl)phenyl at N-2. Subnanomolar IC50 values at the AT(1) receptor subtype were observed for a variety of acylsulfonamides, including aroyl, heteroaroyl, and cycloalkylcarbonyl derivatives. Certain other acidic sulfonamides, such as sulfonylcarbamates and disulfimides also displayed high affinity for the AT(1) receptor. In addition, AT(2) binding for some of these compounds was increased by as much as 1000-fold over the corresponding tetrazole (e.g., AT(2) IC50 17 nM for the tert-butyl sulfonylcarbamate 92). When evaluated for inhibition of the AII pressor response, the benchmark benzoylsulfonamide 9 (L-159,913) was efficacious in several species and was superior to losartan (1a) in conscious rhesus monkeys. Several subsequent analogues, including the 2-chlorobenzoyl (18), (3-chlorothiophene-2-yl)carbonyl (51), ((S)-2,2-dimethylcyclopropyl)carbonyl (80), and tert-butoxycarbonyl (92) derivatives, were highly effective in rats, surpassing 9 and losartan in duration of action and/or potency. Compound 18 (L-162,223) displayed very prolonged AII antagonism in the rat model (>24 h at 1 mg/kg iv). At 1 mg/kg po in rats, 18 and 92 (L-162,234) produced 85-87% peak inhibition of the AII pressor response with duration exceeding 6 h. The identification of triazolinone-based sulfonamide derivatives combining high AT(1) affinity, considerably enhanced AT(2) potency, and favorable in vivo properties provides insights relevant to the design of dual AT(1)/AT(2) receptor antagonists.