Non-peptide 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 containing a 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine was prepared via several synthetic routes. Their affinity for angiotensin II receptors was established in a binding assay experiment and in an isolated-organ test. Molecules with small alkyl groups at C-2 and the (methylbiphenylyl)tetrazole moiety at N-3 were the preferred compounds with affinities and potencies in the nanomolar range. Variations at the N-5 position modulate the activity. Substitution at N-5 with various benzyl groups led to derivatives with in vitro potencies in the nanomolar range, which were equivalent to those of losartan in these assays. Replacement of the N-5 hydrogen with acetic acid esters or, in particular, acetamides gave molecules with increased activity. The most potent was 2-butyl-4,5-dihydro-4-oxo-3-[[2'-(1H-tetrazol-5-yl)-4- biphenylyl]methyl]-3H-imidazo[4,5-c]pyridine-5- (N,N-diethylacetamide) (14u), which is superior to L-158,809 in vitro. Two prototypes were selected as their potassium salts for in vivo testing as antihypertensives. Compounds 14a (EMD 61,650) and 14q (EMD 66,684) reduced blood pressure dose dependently in spontaneously hypertensive rats when administered iv. In this assay, acetamide 14q is superior to losartan.
Mederski
W W
WW
Department of Chemistry, E. Merck, Darmstadt, Germany.
Dorsch
D
D
Bokel
H H
HH
Beier
N
N
Lues
I
I
Schelling
P
P
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D019808:Losartan; D008297:Male; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C087563:EMD 66684; C087564:2-butyl-4-oxo-4,5-dihydro-3-((2'-(1H-tetrazol-5-yl)-4-biphenylyl)methyl)-3H-imidazo(4,5-c)pyridine-5-(N,N-diethylacetamide); D019808:Losartan