Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Scheiper, Bodo; Matter, Hans; Steinhagen, Henning; Stilz, Ulrich; Böcskei, Zsolt; Fleury, Valérie; McCort, Gary

doi:10.1016/j.bmcl.2010.08.092

Cited by 45 publications

(42 citation statements)

References 23 publications

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“…Optimization of the mostly hydrophobic interactions inside the S 3 sp, noticeably improved binding affinity for renin, and selectivity in comparison to related aspartic peptidases 37 . But the corresponding vector for the indole scaffold is a little deviating from the narrow entrance into this subpocket, which might explain the less pronounced effect of this substitution compared to other series like Aliskiren analogs 24,38,39 .…”

Section: Comfa Comsia and Docking Interpretationmentioning

confidence: 90%

“…The blue contour coat O or C-linker in phenoxy or benzyl substitutions indicates this order of activity: 13 (R 1 = benzyl, IC 50 = 0.091) > 1 (R 1 = phenoxy, IC 50 = 0.420), and 14 (IC 50 = 0.009) > 12 (IC 50 = 0.011), also O-linker is electronwithdrawing whereas O in Gly217 is electronegative and prefers to interact with a more electropositive group. Also it can be on the electrostatic repulsion of lone pair of O in phenoxy with lone pair of carboxamide oxygen 24 . In hydrophobic contour maps, the yellow regions are near 4-7th positions of indole core, indicating hydrophobic groups are favored to increase activity, due to the hydrophobic nature of neighbor side chains in S 3 , in such a way that in addition to steric effects, activity of compound 38 (6-OCH 2 CH 2 OPh, IC 50 = 0.024) is higher than compounds 39 (6-OCH 2 CH 2 OH, IC 50 = 0.031), and 40 (6-SO 2 CH 3 , IC 50 = 0.044).…”

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confidence: 99%

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Docking alignment-3D-QSAR of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Ghasemi

Pirhadi

2011

Collect. Czech. Chem. Commun.

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Using generated conformations from docking analysis by CDOCKER algorithm, some 3D-QSAR models; CoMFA region focusing (CoMFA-RF) and CoMSIA have been created on a series of a new class of potent and non-chiral renin inhibitors. The satisfactory predictions were obtained by CoMFA-RF and CoMSIA based on docking alignment in comparison to CoMFA. Robustness and predictability of the models were further verified by using the test set, cross validation (leave one out and leave ten out), bootstrapping, and progressive scrambling. All-orientation search (AOS) strategy was used to acquire the best orientation and minimize the effect of the initial orientation of aligned compounds. The results of 3D-QSAR models are in agreement with docking results. Moreover, the resulting 3D CoMFA-RF/ CoMSIA contour maps and corresponding models were applied to design new and more active inhibitors.Hypertension is a main risk feature of high occurrence worldwide for cardiovascular diseases 1 . Different signals, for instance a drop in blood pressure, a decrease in the plasma sodium, or a reduction in the circulating volume, stimulate the release of renin from kidney 2 . Renin is an aspartic acid protease in the beginning of renin angiotensin system (RAS) cascade, one of the key regulators of blood pressure. The only known natural substrate for renin is angiotensinogen, and renin cleaves it to form a decapeptide, angiotensin I. Then angiotensin converting enzyme (ACE) catalyses conversion of angiotensin I to an octapeptide vasoconstrictor angiotensin II, which has a direct action on proximal tubule, to increase reabsorbing sodium and moreover motivate adrenal cortex to sprinkle aldostrone, that in turn acts upon the distal nephron to retain sodium leading to fluid retention 3 . ACE inhibitors, increase the level of angiotensin I, and do not block manufacture of angiotensin II, that are independent from ACE. Also ACE is

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Section: Comfa Comsia and Docking Interpretationmentioning

confidence: 90%

mentioning

confidence: 99%

Docking alignment-3D-QSAR of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Ghasemi

Pirhadi

2011

Collect. Czech. Chem. Commun.

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“…16). 55 As described above, many companies have invested time and money in researching and producing hundreds of compounds demonstrating good renin inhibitor activity. However, all of them failed to meet the clinical development program so far.…”

Section: K Ramya Et Al Bioorganic and Medicinal Chemistry XXX (Xxxx)mentioning

confidence: 99%

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Ramya

Suresh

Kumar

et al. 2020

Bioorganic & Medicinal Chemistry

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Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin-angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

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“…In route k, the mentioned reagents act as previous reactions, and the NMM is used as a catalytic base. HoAt is used in biological reactions as a peptide coupler [32]. In 2014, Boldron et al, using previous methods and relatively simple reagents (route l), succeeded in synthesizing N- [6-(4-butanoyl-5-…”

Section: Synthetic Strategies Of Indole 2 and 3-carboxamidesmentioning

confidence: 99%

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

Chehardoli

Bahmani

2020

Mol Divers

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Indole derivatives have been the focus of many researchers in the study of pharmaceutical compounds for many years. Researchers have investigated the effect of carboxamide moiety at positions 2 and 3, giving unique inhibitory properties to these compounds. The presence of carboxamide moiety in indole derivatives causes hydrogen bonds with a variety of enzymes and proteins, which in many cases, inhibits their activity. In this review, synthetic strategies of indole 2 and 3-carboxamide derivatives, the type, and mode of interaction of these derivatives against HLGP, HIV-1, renin enzyme, and structure-activity studies of these compounds were investigated. It is hoped that indole scaffolds will be tested in the future for maximum activity in pharmacological compounds.

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Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Cited by 45 publications

References 23 publications

Docking alignment-3D-QSAR of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Docking alignment-3D-QSAR of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

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