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Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy.
Simoneau B,
Lavallée P,
Anderson PC,
Bailey M,
Bantle G,
Berthiaume S,
Chabot C,
Fazal G,
Halmos T,
Ogilvie WW,
Poupart MA,
Thavonekham B,
Xin Z,
Thibeault D,
Bolger G,
Panzenbeck M,
Winquist R,
Jung GL.
Boehringer Ingelheim (Canada) Ltd., Bio-Méga Research Division, Laval, Québec. bsimoneau@bio-mega.boehringer-ingelheim.ca
A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.
PMID: 10220035 [PubMed - indexed for MEDLINE]
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Cited by 3 PubMed Central articles
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Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction.
Veerappan A, Reid AC, Estephan R, O'Connor N, Thadani-Mulero M, Salazar-Rodriguez M, Levi R, Silver RB.
Proc Natl Acad Sci U S A. 2008 Jan 29; 105(4):1315-20. Epub 2008 Jan 17.
[Proc Natl Acad Sci U S A. 2008]
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Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion.
Mackins CJ, Kano S, Seyedi N, Schäfer U, Reid AC, Machida T, Silver RB, Levi R.
J Clin Invest. 2006 Apr; 116(4):1063-70.
[J Clin Invest. 2006]
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Mast cells: a unique source of renin.
Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R.
Proc Natl Acad Sci U S A. 2004 Sep 14; 101(37):13607-12. Epub 2004 Sep 1.
[Proc Natl Acad Sci U S A. 2004]