Discovery of Inhibitors of Human Renin with High Oral Bioavailability

Hoover, Dennis J.; Lefker, Bruce A.; Rosati, Robert L.; Wester, Ronald T.; Kleinman, Edward F.; Bindra, Jasjit S.; Holt, William F.; Murphy, William R.; Mangiapane, Michael L.; Hockel, Gregory M.; Williams, Ian H.; Smith, Ward H.; Gumkowski, Michael J.; Shepard, Richard M.; Gardner, Mark; Nocerini, Mark R.

doi:10.1007/978-1-4615-1871-6_21

Cited by 17 publications

(13 citation statements)

References 34 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We repeated the experiment with several control compounds: LY2886721 ( 5 ), Eli Lilly & Co.'s second-generation clinical candidate, which does not inhibit purified CatD in vitro (IC 50 >100 μM) 34 ; LY2811376 ( 1 ), which inhibits both BACE1 and CatD; and CP-108671 ( 7 ) (ref. 35 ), a pepstatin-based renin inhibitor with potent off-target CatD inhibition, but no BACE1 activity ( Supplementary Fig. 3 ).…”

Section: Resultsmentioning

confidence: 99%

Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

et al. 2016

View full text Add to dashboard Cite

Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.

show abstract

Section: Resultsmentioning

confidence: 99%

Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Furthermore, 4-(methoxymethylene)-1-methylpiperidine (2) not only can be produced on a larger scale, but also allows smooth separation from the Wittig by-product, triphenylphosphine, through sophisticated workup. 5 4-Formyl-1-piperidinecarboxylic acid-1,1-dimethylethyl ester (8) was prepared in a similar way according to the patent literature, 6 i.e., starting from 4-oxo-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (6) 7 via the enol ether intermediate which was accessible by a Wittig reaction (Table 1, X = N-COO-t-Bu). 2H-Tetrahydrothiopyran-4-carboxaldehyde (14) proved to be difficult to synthesize.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of novel 3-heterospiro[5.5]undecanes

Fröhlich¹,

Sauter²,

Hametner³

et al. 2009

Arkivoc

View full text Add to dashboard Cite

Synthetic strategies leading to novel 3-heterospiro[5.5]undecan-9-ones are described. Starting from aliphatic 4-substituted heterocyclic aldehydes (1-methyl-4-piperidine carboxaldehyde, 4-formyl-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 2H-tetrahydrothiopyran-4-carboxaldehyde, and 2H-tetrahydropyran-4-carboxaldehyde) 3-heterospiro[5.5]undec-7-en-9-ones were made by Robinson annelation and upon further hydrogenation gave the desired 3-heterospiro[5.5]undecan-9-ones.

show abstract

“…Several renin inhibitors have been identified since the 1980s, including enalkiren [79], CGP 38560 [80], remikiren [81], zankiren [82], ciprokiren [83], terlakiren [84], FK906 [85] and A-74273 [86]. Their efficacy in inhibiting renin and lowering blood pressure was demonstrated in animal experiments, although species specificity has somewhat limited in vivo animal studies.…”

Section: Tolerability and Safety Of Renin Inhibitors In Clinical Studymentioning

confidence: 99%

Potential side effects of renin inhibitors – mechanisms based on comparison with other renin–angiotensin blockers

Cheng

Harris

2006

Expert Opinion on Drug Safety

View full text Add to dashboard Cite

Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.

show abstract

Discovery of Inhibitors of Human Renin with High Oral Bioavailability

Cited by 17 publications

References 34 publications

Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

Synthesis of novel 3-heterospiro[5.5]undecanes

Potential side effects of renin inhibitors – mechanisms based on comparison with other renin–angiotensin blockers

Contact Info

Product

Resources

About