Design and optimization of renin inhibitors: Orally bioavailable alkyl amines

Tice, Colin M.; Xu, Zhixiang; Yuan, Jing; Simpson, R. David; Cacatian, Salvacion; Flaherty, Patrick; Zhao, Wei; Guo, Joan; Ishchenko, Alexey; Singh, Suresh B.; Wu, Zhenyong; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Mason, J. L.; Panemangalore, Reshma; Cappiello, Maria Grazia; Müller, Dominik N.; Harrison, Richard K.; McGeehan, Gerard M.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A.

doi:10.1016/j.bmcl.2009.04.140

Cited by 18 publications

(15 citation statements)

References 15 publications

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“…This trend can be explained based on the fact that most reported potent renin inhibitors (including those in our training list) tend to have large molecular sizes Table 6 The training compounds used for adding excluded spheres for Hypo1/5 and Hypo1/7 using HIPHOP-REFINE module of CATALYST. (of MW > 600) [16,18,7,19,[63][64][65] and therefore require wellbalanced combination of hydrophobic and hydrophilic groups. Lack of such balance for such large molecules can lead to excessive hydration at one end, or poor water-solubility at the other, which in both cases seem to undermine their affinities to renin.…”

Section: Qsar Modelingmentioning

confidence: 99%

“…Fitting the hydroxyl fragment of the co-crystallized ligand in 3GW5 complex (ligand PDB code: 72X) [64] against HBA feature in Hypo1/7 (Fig. 7a) corresponds to hydrogen-bonding interactions connecting this fragment with the hydroxy side chain of SER230.…”

Section: Comparing Pharmacophore Models With Crystallographic Complexesmentioning

confidence: 99%

“…To further emphasize the validity of our pharmacophore/QSAR modeling approach, we compared the crystallographic structures of two renin/ligand complexes (PDB codes: 3GW5 and 3D91 at resolutions of 2.0Å and 2.2Å, respectively) [64,65] with Hypo1/7 and Hypo1/5. Figs.…”

Section: Comparing Pharmacophore Models With Crystallographic Complexesmentioning

confidence: 99%

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Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

Al-Nadaf

Taha

2011

Journal of Molecular Graphics and Modelling

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Section: Qsar Modelingmentioning

confidence: 99%

Section: Comparing Pharmacophore Models With Crystallographic Complexesmentioning

confidence: 99%

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Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

Al-Nadaf

Taha

2011

Journal of Molecular Graphics and Modelling

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“…Several other novel potent, non-peptidic, bioavailable DRIs are currently being developed, but are in the early stages of clinical testing. [34,35] Results of numerous clinical trials have shown that aliskiren reduces plasma renin activity when administered alone and also neutralizes the reactive rise in plasma renin activity seen with ACE inhibitors, ARBs, diuretics, or CCBs. [30,31,[36][37][38][39][40][41][42][43][44][45][46][47][48][49] Specifically, monotherapy with ACE inhibitors or ARBs increased plasma renin activity from baseline by >100%, whereas aliskiren alone or in combination with these drug classes reduced plasma renin activity by approximately 50-70%.…”

Section: Effect Of Direct Renin Inhibitors On Raas Components and Potmentioning

confidence: 99%

The Role of Direct Renin Inhibition in Clinical Practice

Rashid

Mende

2011

American Journal Cardiovascular Drugs

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Monotherapy with most antihypertensive agents reduces systolic BP by about 10 mmHg ('Rule of 10'). Thus, the majority of hypertensive patients require combination therapy to achieve BP goals. In this review, we provide a brief overview of the renin-angiotensin-aldosterone system (RAAS) and discuss the rationale, clinical evidence, and shortcomings related to the use of angiotensin-converting enzyme (ACE) inhibitors in combination with angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We summarize the rationale and clinical evidence supporting the use of the direct renin inhibitor (DRI) aliskiren, particularly in combination with other antihypertensive classes, including in high-risk patients with diabetes mellitus and with or without diabetic nephropathy. DRIs may be useful in combination with ACE inhibitors or ARBs as they provide a more complete blockade of the RAAS, effectively suppressing residual angiotensin II production and the counter-regulatory increase in plasma renin activity observed in patients receiving monotherapy with ACE inhibitors or ARBs.

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“…19,20 Thus, in both cases, the protonated secondary amine is positioned between the catalytic aspartates, Asp32 and Asp215. The urea and carbamate NH's both donate hydrogen bonds to the backbone carbonyl oxygen of Gly217.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

Jia¹,

Simpson²,

Yuan³

et al. 2011

ACS Med. Chem. Lett.

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Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

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Design and optimization of renin inhibitors: Orally bioavailable alkyl amines

Cited by 18 publications

References 15 publications

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

The Role of Direct Renin Inhibition in Clinical Practice

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

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