Piperidine renin inhibitors: from leads to drug candidates

Märki, Hans Peter; Binggeli, Alfred; Bittner, Beate; Bohner-Lang, V; Breu, Volker; Bur, Daniel; Coassolo, Philippe; Clozel, Jean‐Paul; D’Arcy, Allan; Doebeli, H; Fischli, Walter; Funk, Christoph; Foricher, Joseph; Giller, Thomas; Grüninger, Fiona; Guenzi, Alberto; Güller, Rolf; Hartung, Thomas; Hirth, Georges; Jenny, Christian; Kansy, Manfred; Klinkhammer, Uwe; Lavé, Th.; Lohri, Bruno; Luft, Friedrich C.; Mervaala, Eero; Müller, Dominik N.; Müller, Marcel; Montavon, François; Oefner, Christian; Qiu, Chunhua; Reichel, Anton; Sanwald-Ducray, Patricia; Scalone, Michelangelo; Schleimer, Michael; Schmid, Rudolf; Stadler, Heinz; Treiber, Alexander; Valdenaire, Olivier; Vieira, Eric; Waldmeier, Pius; Wiegand-Chou, R; Wilhelm, M; Wostl, Wolfgang; Zell, Manfred; Zell, Reinhard

doi:10.1016/s0014-827x(01)01004-7

Cited by 58 publications

(31 citation statements)

References 21 publications

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“…However, these RIs had poor bioavailability, had short duration of action and were not suitable for clinical use due to lack of oral bioavailability. Marki et al reported a novel, nonpeptidic renin inhibitor (RI) of the piperidine type that was synthetically optimized and was much improved in potency as well as physicochemical and metabolic properties over the earlier peptidomimetic renin inhibitors [18]. Our results confirm the data from Marki et al that demonstrated this piperidine RI lowered BP and also normalized microalbuminuria and kidney end organ damage in double transgenic rats harboring both the human angiotensinogen and renin genes.…”

Section: Discussionsupporting

confidence: 85%

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A Nonpeptide, Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

Major

Olszewski

Rosebury

et al. 2008

Cardiovasc Drugs Ther

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In the dTGM, PRA, plasma aldosterone, GFR, microalbuminuria and left ventricular free wall thickness (LVH) were higher than in the wild type C57BL/6 mice. Microalbuminuria and LVH were significantly reduced by 93% and 9% for the RI, 83% and 13% for enalapril and 73% and 6% for candesartan, respectively. PRA and aldosterone were reduced by the RI 56% and 23%, respectively. These results suggest that the RI provides protection against cardiac and renal disease, similar to ARB and ACEI.

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Section: Discussionsupporting

confidence: 85%

“…The piperidine RI (4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-3-oxo-piperidine-1-carboxylic acid tertbutyl ester) was from the Pfizer Chemistry Department based on the previously published synthetic description [18]. Enalapril maleate was obtained from Sigma Chemical Co. (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

A Nonpeptide, Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

Major

Olszewski

Rosebury

et al. 2008

Cardiovasc Drugs Ther

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“…This effect of renin inhibitors seems to depend on the lipophilicity, efficacy (IC 50 /K i ) and chemical structure of the compounds, since RO0663525, a nonpeptidomimetic representative of the piperidine class of inhibitors Oefner et al, 1999;Maerki et al, 2001), but not the more hydrophilic peptidomimetics remikiren and pepstatin, was efficient. Pepstatin is a better inhibitor of cathepsin D than of renin (Baldwin et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that an alternative transcription site for renin may be used in the brain, which would result, if transcribed, in the production of an altered form of prorenin mRNA, not secreted and constitutively active (Lee-Kirch et al, 1999;Sinn and Sigmund, 2000). Alternatively, it has been shown that the binding of piperidine inhibitors to the renin active site pocket results in an induced structural fit of the enzyme, which has not been demonstrated for peptidomimetic inhibitors (Deinum et al, 1998;Vieira et al, 1999;Maerki et al, 2001). This conformational change may modify the binding of renin/prorenin to its recently described renin receptor (Nguyen et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

Juillerat‐Jeanneret¹,

Célérier

Bernasconi³

et al. 2004

Br J Cancer

131

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The expression and function in growth and apoptosis of the renin -angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT 2 and/or AT 1 mRNAs and proteins determined by RT -PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1 -14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.

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“…The ability of piperidine derivatives to function as inhibitors of the aspartyl protease renin was first discovered by the Roche group through a high throughput screening effort [123][124][125][126]. X-ray crystal structure data for piperidine inhibitors complexed to renin showed that the protonated piperidine nitrogen was positioned between the two catalytic aspartic acid residues (Fig.…”

Section: Piperidinesmentioning

confidence: 99%

Progress in the Discovery of BACE Inhibitors

Thompson¹,

Bronson²,

Zusi³

2005

CPD

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Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of beta-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.

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Piperidine renin inhibitors: from leads to drug candidates

Cited by 58 publications

References 21 publications

A Nonpeptide, Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

A Nonpeptide, Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

Progress in the Discovery of BACE Inhibitors

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