NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A SERIES OF NOVEL 4,5-DIHYDRO-4-OXO-3H-IMIDAZO[4,5-C]PYRIDINE DERIVATIVES

A series of novel non-peptide angiotensin II receptor antagonists cont aining a 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyrid ine was prepared via several synthetic routes. Their affinity for angi otensin II receptors was established in a binding assay experiment and in an isolated-organ test. Molecules with small alkyl groups at C-2 a nd the (methylbiphenylyl) tetrazole moiety at N-3 were the preferred c ompounds with affinities and potencies in the nanomolar range. Variati ons at the N-5 position modulate the activity. Substitution at N-5 wit h various benzyl groups led to derivatives with in vitro potencies in the nanomolar range, which were equivalent to those of losartan in the se assays. Replacement of the N-5 hydrogen with acetic acid esters or, in particular, acetamides gave molecules with increased activity. The most potent was 3H-imidazo[4,5-c]pyridine-5-(N,N-diethylacetamide) (1 4u), which is superior to L-158,809 in vitro. Two prototypes were sele cted as their potassium salts for in vivo testing as antihypertensives . Compounds 14a (EMD 61 650) and 14q (EMD 66 684) reduced blood pressu re dose dependently in spontaneously hypertensive rats when administer ed iv. In this assay, acetamide 14q is superior to losartan.