SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF A NEW SERIES OF POTENT AT(1) SELECTIVE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - 5-(BIPHENYL-4-YLMETHYL)PYRAZOLES

The synthesis and pharmacological activity of a new series of 5-(biphe nyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of[H-3]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium -depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requiremen ts derived from related structure-activity relationship studies. A pro pyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different gr oups at position 3 (H, small alkyl, phenyl, benzyl) provided good bind ing affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tes ted in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n ,1'-biphenyl-4-yl]methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo ( iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at I mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent .