Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of spirocyclic piperidines

Chen, Austin; Aspiotis, Renée; Campeau, Louis‐Charles; Cauchon, Elizabeth; Chefson, Amadine; Ducharme, Yves; Falgueyret, Jean‐Pierre; Gagné, Sébastien; Han, Yongxin; Houle, Robert; Laliberté, Sébastien; Larouche, Guillaume; Lévesque, Jean-François; McKay, Dan; Percival, David

doi:10.1016/j.bmcl.2011.10.013

Cited by 16 publications

(8 citation statements)

References 8 publications

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“…The degree of complexity associated with efforts to abrogate CYP3A4 TDI while maintaining potency and PK attributes is illustrated with a series of potent renin inhibitors (Figure ). , Lead compounds 27 and 28 and several related analogues were identified as time-dependent inhibitors of CYP3A4 (e.g., compound 27 , 110 fold shift in CYP3A4 IC 50 over a 30 min incubation period, k inact = 0.094 min –1 , K I = 3.2 μM). Trapping studies in HLM using exogenous nucleophiles (e.g., GSH, cyanide, and semicarbazide) did not prevent CYP3A4 TDI, and were not fruitful in providing insights into the RM responsible for CYP inactivation.…”

Section: Medicinal Chemistry Tactics Toward Minimizing/eliminating Cy...mentioning

confidence: 99%

Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks

Orr¹,

Ripp²,

Ballard³

et al. 2012

J. Med. Chem.

174

183

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Section: Medicinal Chemistry Tactics Toward Minimizing/eliminating Cy...mentioning

confidence: 99%

Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks

Orr¹,

Ripp²,

Ballard³

et al. 2012

J. Med. Chem.

174

183

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“…67−70 Chemicals containing 8-methylquinoline were more possible to be time-dependent inhibitors of CYP3A4 due to the formation of an active metabolite capable of binding irreversibly to the CYP enzymes. 52 In addition, the compounds possessing more polar capping groups such as sulfonyl tended to exhibit CYP3A4 TDI. 71 The TDI effect was believed to be related to the demethylation of the 4-OCH 3 or 3-OCH 3 group on the chemicals containing 5-methoxy-2,4dimethylpyrimidine where a second oxidative metabolism step might produce quinone intermediates that can react with nucleophiles.…”

Section: Molecularmentioning

confidence: 99%

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

et al. 2022

Mol. Pharmaceutics

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Cytochrome P450 3A4 (CYP3A4) is one of the major drug metabolizing enzymes in the human body and metabolizes ∼30–50% of clinically used drugs. Inhibition of CYP3A4 must always be considered in the development of new drugs. Time-dependent inhibition (TDI) is an important P450 inhibition type that could cause undesired drug–drug interactions. Therefore, identification of CYP3A4 TDI by a rapid convenient way is of great importance to any new drug discovery effort. Here, we report the development of in silico classification models for prediction of potential CYP3A4 time-dependent inhibitors. On the basis of the CYP3A4 TDI data set that we manually collected from literature and databases, both conventional machine learning and deep learning models were constructed. The comparisons of different sampling strategies, molecular representations, and machine-learning algorithms showed the benefits of a balanced data set and the deep-learning model featured by GraphConv. The generalization ability of the best model was tested by screening an external data set, and the prediction results were validated by biological experiments. In addition, several structural alerts that are relevant to CYP3A4 time-dependent inhibitors were identified via information gain and frequency analysis. We anticipate that our effort would be useful for identification of potential CYP3A4 time-dependent inhibitors in drug discovery and design.

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“…The applied methods are specified later in the syntheses section. Physicochemical properties of the inhibitors 7, 11, 18, 25, as well as newly synthesized intermediates 1, 3,4,6,9,12,13,14,15,16,17,19,20,21,22,23,24, are presented in Tables 2 and 3.…”

Section: Chemistrymentioning

confidence: 99%

“…Reagents Boc-Phe(4-OMe)-OH, Boc-N-Me-Leu-OH porcine kidney renin and N-acetylrenin substrate tetradecapeptide were acquired from recognized vendor. The AHGHA, AHPPA, and AAHOA (1,12,19) were synthesized according to the Maibaum protocol. Solvents were of analytical purity.…”

Section: Chemistrymentioning

confidence: 99%

“…Therefore, new-generation inhibitors that do not contain an unstable peptide linkage (-CONH-), which is susceptible to enzymatic degradation, were designed in order to overcome the aforementioned problems. Non-peptidic renin inhibitors include aliskiren and a novel class of inhibitors that are piperidine derivatives [12][13][14]. In our opinion, it is important that the inhibitors would have ability to form hydrogen bonds with the -CONH-moiety, which could result in increased inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

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Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

Winiecka

Jaworski

Mazurek

et al. 2016

Journal of Peptide Science

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In search for new drugs lowering arterial blood pressure, which could be applied in anti-hypertensive therapy, research concerning agents blocking of renin-angiotensin-aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8-13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N-methylleucyl-β-hydroxy-γ-amino acids at the P2-P1' position: 4-[N-(N-methylleucyl)-amino]-3-hydroxy-7-(3-nitroguanidino)-heptanoic acid (AHGHA), 4-[N-(N-methylleucyl)-amino]-3-hydroxy-5-phenyl-pentanoic acid (AHPPA) or 4-[N-(N-methylleucyl)-amino]-8-benzyloxycarbonylamino-3-hydroxyoctanoic acid (AAHOA). The previously listed synthetic β-hydroxy-γ-amino acids constitute pseudodipeptidic units that correspond to the P1-P1' position of the inhibitor molecule. An unnatural amino acid, 4-methoxyphenylalanin (Phe(4-OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'-P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc-Phe(4-OMe)-MeLeu-AHGHA-OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10(-6)-10(-9) M. The compound Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa proved to be the most active (IC50 = 1.05 × 10(-9) M). The compounds Boc-Phe(4-OMe)-MeLeu-AHGHA-Ahx-Iaa and Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa are resistant to chymotrypsin.

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Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of spirocyclic piperidines

Cited by 16 publications

References 8 publications

Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks

Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

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