A new class of orally active glycol renin inhibitors containing phenyllactic acid at P3.
We prepared a new series of renin inhibitors based on dipeptide glycols, replacing the P4-P3 subsites with an O-(N-morpholinocarbonyl)-3-L-phenyllactic acid residue. This modification proved bioisosteric with Boc-L-phenylalanine, giving rise to highly potent human renin inhibitors (1-5 nM), e.g., SC-46944 (IC50 = 5 nM). Moreover, this change produced compounds that are orally efficacious in reducing plasma renin activity in salt-depleted marmosets.
Hanson
G J
GJ
G.D. Searle and Co. Skokie, Ill. 60077.
Baran
J S
JS
Lowrie
H S
HS
Russell
M A
MA
Sarussi
S J
SJ
Williams
K
K
Babler
M
M
Bittner
S E
SE
Papaioannou
S E
SE
Yang
P C
PC
D000818:Animals; D002143:Callitrichinae; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D006018:Glycols / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007773:Lactates; D008968:Molecular Conformation; D015394:Molecular Structure; D009025:Morpholines / Q000494:pharmacology; D012083:Renin / Q000097:blood; D000092502:Renin Inhibitors
D004151:Dipeptides; D006018:Glycols; D007773:Lactates; D009025:Morpholines; D012083:Renin; D000092502:Renin Inhibitors; C059279:O-(N-morpholinocarbonyl)-3-phenyllactic acid; C059277:SC 46944