Non-peptide renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 replacements.
A series of novel renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 surrogates are presented. The P2-P3 mimetics were obtained from (omega-phenylalkyl)-phosphinic acids 1a-c and 2-hydroxyalkanoic acid benzyl esters 2a-f by N,N'-dicyclohexylcarbodiimide-mediated coupling and subsequent oxidation with sodium metaperjodate. Ester cleavage of these derivatives and coupling with P1-P1' transition-state mimetics I-VII provided highly selective compounds with inhibitory potencies in the lower nanomolar range. Small renin inhibitors, such as analogues 8c and 8h with molecular weights of 539 and 537, respectively, could be prepared. These compounds exhibited IC50 values of about 20 nM against human plasma renin. Compound 7i was examined in vivo for its hypotensive effect. In salt-depleted cynomolgus monkeys, 7i inhibited plasma renin activity almost completely and lowered blood pressure after oral administration of a dose of 30 mg/kg.
Raddatz
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E. Merck Darmstadt, Germany.
Minck
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Rippmann
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Schmitges
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CJ
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010434:Pepsin A / Q000037:antagonists & inhibitors; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D012083:Renin / Q000097:blood / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D002402:Cathepsin D; D009943:Organophosphorus Compounds; D010434:Pepsin A; D011392:Proline; D012083:Renin; D000092502:Renin Inhibitors; C054518:ceronapril