PMID: 2105396Feb 1, 1990Paper

New inhibitors of renin that contain novel phosphostatine Leu-Val replacements

Journal of Medicinal Chemistry
J F DellariaT J Perun

Abstract

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).

Citations

Oct 6, 2006·Organic Letters·Rajasekhar Dodda, Cong-Gui Zhao
Jun 8, 2006·Journal of the American Chemical Society·Sampak Samanta, Cong-Gui Zhao
Sep 11, 2012·The Journal of Organic Chemistry·Xiaoming TaoZhaoguo Zhang
Mar 11, 2004·Chemical Communications : Chem Comm·Mario OrdóñezAngelina González-Morales
Sep 16, 2011·Advanced Synthesis & Catalysis·Sandun PereraCong-Gui Zhao
Mar 26, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mario OrdóñezVictoria Labastida-Galván
Nov 8, 2008·Chemistry : a European Journal·Xiaohong ChenChangwei Hu
Dec 17, 2009·Chemistry : a European Journal·Łukasz AlbrechtKarl Anker Jørgensen
Jun 28, 2013·Organic & Biomolecular Chemistry·Tommaso AngeliniLuigi Vaccaro
Sep 28, 2012·Archiv der Pharmazie·Kalla Reddi Mohan NaiduOla Lasekan
Oct 21, 2014·Organic & Biomolecular Chemistry·Yong-Ming SunLi-Biao Han
Nov 16, 2007·The Journal of Physical Chemistry. a·Marek DoskoczJerzy Leszczynski
Dec 9, 2004·Chemical Reviews·Kristof MoonenChristian V Stevens
Sep 4, 2021·Organic & Biomolecular Chemistry·Manish K JaiswalRavi P Singh
Oct 25, 2001·The Journal of Organic Chemistry·Allen A. Thomas, K. Barry Sharpless

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