New inhibitors of renin that contain novel phosphostatine Leu-Val replacements.
A novel series of renin inhibitors based on the Phe8-His9-Leu10-Val11 substructure of renin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe8-His9 portion of the native substructure and employ novel phosphostatine Leu10-Val11 replacements (LVRs). The phosphostatine LVRs were prepared by condensing a dialkyl phosphonate ester stabilized anion with either N-t-Boc-amino aldehydes or N-tritylamino aldehydes (derived from the corresponding amino acid). Structure-activity relationships at the Leu10 side chain revealed that the LVR derived from L-cyclohexylalanine provided a 130-fold boost in potency over the LVR derived from L-leucine. The dialkyl ester moiety was varied and a loss in potency was incurred when the alkyl ester was chain extended or alpha-branched; dimethyl esters provided optimum potency. The phosphonate moiety was replaced by a half-acid half-ester phosphonate and dimethylphosphinate; both replacements lead to a loss in potency. The more potent inhibitors (IC50 = 20-50 nM) were found to be selective inhibitors for renin over porcine pepsin and bovine cathepsin D (little or no inhibition was observed at 10(-5) M).
Dellaria
J F
JF
Abbott Laboratories, Pharmaceutical Products Division D-47K, Abbott Park, Illinois 60064.
Maki
R G
RG
Stein
H H
HH
Cohen
J
J
Whittern
D
D
Marsh
K
K
Hoffman
D J
DJ
Plattner
J J
JJ
Perun
T J
TJ
D000596:Amino Acids; D000818:Animals; D000959:Antihypertensive Agents; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D002417:Cattle; D066298:In Vitro Techniques; D007930:Leucine; D010434:Pepsin A / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014633:Valine; D000092502:Renin Inhibitors
D000596:Amino Acids; D000959:Antihypertensive Agents; D002402:Cathepsin D; D007930:Leucine; D010434:Pepsin A; D011480:Protease Inhibitors; D014633:Valine; D000092502:Renin Inhibitors; C013165:statine