SULFONYLUREAS AND SULFONYLCARBAMATES AS NEW NON-TETRAZOLE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - DISCOVERY OF A HIGHLY POTENT ORALLY-ACTIVE (IMIDAZOLYLBIPHENYLYL) SULFONYLUREA (HR-720)

The synthesis and pharmacological activity of new potent nonpeptide no n-tetrazole angiotensin II (AII) receptor antagonists are described. T hese compounds are 4-thioimidazole derivatives linked on N-1 to a biph enylsulfonyl fragment by a methylene spacer. Different acidic sulfonam ides such as sulfonylureas 12, sulfonylcarbamates 15, sulfonylamides 1 6, and sulfonylsulfonamides 17 have been investigated as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Thei r activity were evaluated by AII receptor binding assay as well as by in vivo (iv and po) assays such as inhibition of the AII-induced press er response in pithed rats. Most of the synthesized sulfonyl derivativ es showed nanomolar affinity for the AT(1) receptor subtype. The N-pro pylsulfonylurea 12d and the ethyl sulfonylcarbamate 15b as representat ive members of this series exhibited high oral activity in the pithed rat model with ID50 values of 0.38 and 0.4 mg/kg, respectively. Struct ure-activity relationships on the imidazole ring linked to the methylb iphenyl N-propylsulfonylurea fragment demonstrated similar features to those found in the corresponding tetrazole series. For both class of compounds, the linear butyl chain in position 2 and a carboxylic acid in position 5 were important for high in vitro and in vivo activity. I n most cases, replacement of the carboxylic acid was detrimental to in vivo activity while maintaining the in vitro binding affinity. Introd uction of a methylthio group in position 4 was found to enhance oral a ctivity compared to compounds with chloro or other alkylthio, (polyflu oroalkyl)thio, and arylthio groups. 2-Butyl-4-(methylthio)- 1-[[2'-[[[ (propylamino)carbonyl]amino]sufonyl] '-biphenyl)-4-yl]methyl]-1H-imida zole-5-carboxylic acid (12d) as the most promising example of the seri es was synthesized as its dipotassium salt (50, HR 720). This compound 50 inhibited the specific binding of [I-125]-AII to rat liver membran es with an IC50 value of 0.48 nM. In, vivo, 50 dose-dependently inhibi ted the AII-induced presser response in normotensive pithed rats (ID50 = 0.11 mg/kg iv and 0.7 mg/kg po). In addition, this compound produce d a marked and long-lasting decrease in blood pressure in high renin a nimal models and proved to be superior to the corresponding tetrazole 45 as well as to DuP 753 or its active metabolite EXP 3174. Compound 5 0 has been selected for in-depth investigations and is currently under going phase II clinical trials.