- Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors
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Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC 50 of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
- Bezen?on, Olivier,Bur, Daniel,Weller, Thomas,Richard-Bildstein, Sylvia,Remeň, Lubo?,Sifferlen, Thierry,Corminboeuf, Olivier,Grisostomi, Corinna,Boss, Christoph,Prade, Lars,Delahaye, Stéphane,Treiber, Alexander,Strickner, Panja,Binkert, Christoph,Hess, Patrick,Steiner, Beat,Fischli, Walter
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supporting information; experimental part
p. 3689 - 3702
(2010/04/02)
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- BICYCLONONENE DERIVATIVES AS RENIN INHIBITORS
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The invention relates to novel bicyclononene derivatives of Formula (I); and the use thereof as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.
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Page/Page column 44-45
(2008/06/13)
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- BICYCLONONENE DERIVATIVES
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The invention relates to novel bicyclononene derivatives and the use thereof as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.
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Page/Page column 20-21
(2010/10/20)
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- DIAZABICYCLONONENE DERIVATIVES AND THEIR USE AS RENIN INHIBITORS
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The invention relates to novel derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, p
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Page/Page column 23
(2010/02/11)
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- DIAZABICYCLONONENE AND TETRAHYDROPYRIDINE DERIVATIVES AS RENIN INHIBITORS
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The invention relates to novel bicyclic derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the com
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Page/Page column 34
(2010/02/11)
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- DIAZABICYCLONONENE DERIVATIVES AND THEIR USE AS RENIN INHIBITORS
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The invention relates to novel 3,9-diazabicyclo[3.3.1]nonene derivatives of formula (I), wherein Z is 0 or 1, one of m, n is 0 and the other is 1, and their use as inhibitors of renin.
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Page/Page column 25
(2010/02/12)
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- DIAZABICYCLONONENE AND TETRAHYDROPYRIDINE DERIVATIVES WITH A NEW SIDE-CHAIN
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The invention relates to novel bicyclic derivatives, and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the co
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Page/Page column 23-24
(2010/02/12)
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- TETRAHYDROPYRIDINE DERIVATIVES
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The invention relates to novel tetrahydropyridine derivatives and use thereof as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin. (I) wherein X and Y represent independently hydrogen, fluorine or a methyl group; X and Y do not represent both hydrogen at the same time or X and Y may together form a cyclopropyl ring; W represents a phenyl or a heteroaryl, the heteroaryl ring being a six-membered and non-fused ring, the phenyl ring and the heteroaryl are substituted with V in position 3 or 4; A and B independently represent-O-;-S-;-SO-or-SO2-; U represents aryl or heteroaryl; T represents-CONR1-;-(CH2)pOCO-;-(CH2)pN(R1)CO-;-(CH2)p N(R1)SO2-;-COO-;-(CH2)pOCONR1-or-(CH2)pN(R2)CONR1-; R1 and R2 independently respresent hydrogen; lower alkyl; lower alkenyl; lower alkynil; cycloalkyl; aryl-lower alkyl, heteroaryl-lower alkyl or cycloalkyl-lower alkyl; Q represents lower alkylene or lower alkenylene; M represents hydrogen; cycloalkyl; aryl; heterocyclyl or heteroaryl:
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Page/Page column 24
(2010/02/11)
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