Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2022 Aug 1;13(8):1351–1357. doi: 10.1021/acsmedchemlett.2c00280

Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors

Daisuke Iijima †, Hiroshi Sugama †, Nobumasa Awai †, Yoichi Takahashi †, Yuko Togashi †, Tohru Takebe †, Jianshu Xie ‡, Jingkang Shen ‡, Ying Ke ‡, Hidenori Akatsuka †, Takayuki Kawaguchi †, Kei Takedomi †, Akiko Kashima †, Masashi Nishio †, Yosuke Inui †, Hikaru Yoneda †, Guangxin Xia ‡,*, Toru Iijima †,§,*
PMCID: PMC9377009  PMID: 35978678

Abstract

graphic file with name ml2c00280_0012.jpg

The renin–angiotensin–aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1′–S2′ sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.

Keywords: Renin inhibitor, renin−angiotensin−aldosterone system, SPH3127, binding efficiency index

Hypertension increases the risk of stroke, heart disease, and kidney failure, and these cerebrocardiovascular diseases are the leading causes of death in the developed countries, along with cancer. While recent clinical data have provided accumulating evidence that strict blood pressure control reduces the risk of cerebrocardiovascular events, almost half of the patients do not achieve their blood pressure goal with the current available treatments.1 Therefore, there is an urgent need to identify novel antihypertensive agents with more potent hypotensive effect.

The renin–angiotensin–aldosterone system (RAAS) is known to play a key role in the regulation of blood pressure and renal function.2 A number of clinical studies using angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) have demonstrated that the blocking of the RAAS cascade is effective for controlling blood pressure and is beneficial for organ protection among patients with diseases, such as diabetic nephropathy and heart failure.2 Meanwhile, ACE inhibitors and ARBs increase the plasma renin concentration and the plasma renin activity via a feedback mechanism,3 which may cause RAAS blockade to be insufficient. Because renin is the first and rate-limiting enzyme in the RAAS, direct renin inhibitors (DRIs) should potentially block the cascade completely even in situations of elevated circulating or tissue renin activity,3 meaning renin has long been recognized as a desirable target for potent antihypertensive drugs.

While considerable efforts have been made by pharmaceutical companies to discover DRIs since the early 1980s,4−6 only aliskiren has reached the market for the treatment of essential hypertension. Early DRIs were peptidomimetic compounds, which were designed from the substrate peptide that binds to a wide binding site on renin,7 such as remikiren (1)8 and aliskiren (2).9 Because of their large molecular weights (MW > 500) and high numbers of rotatable bonds and hydrogen bond donors (HBDs), these compounds showed low intrinsic cell permeability and extremely low oral bioavailability, even with commercially available aliskiren (F = 2.6% in humans)10 (Figure 1). Meanwhile, nonpeptidomimetic DRIs have also been comprehensively explored in view of improving oral bioavailability, and as a result of extensive efforts in screening and medicinal chemistry, piperidine derivatives with improved membrane permeability and bioavailability, such as the compounds 3(11) and 4 (ACT-077825),12 have been identified (3, F = 6% in dogs; 4, F = 24% in rats) (Figure 2). However, these piperidine derivatives have a high MW of >600, probably because they need to occupy a different lipophilic region (opened flap region)13,14 in addition to the wide substrate binding site of renin to improve the inhibitory activity. Generally, higher MW compounds have higher lipophilicity, resulting in poor solubility, poor metabolic stability, and high plasma protein binding (PPB). In fact, these piperidine derivatives showed potent inhibitory activity against recombinant human renin (rh-renin) in buffer solutions: however, their high PPB would result in 100-fold attenuation of their inhibitory potency against human plasma renin activity (hPRA), known as a predictor of in vivo hypotensive effect (3, rh-renin IC50 = 0.067 nM, hPRA IC50 = 8.9 nM; 4, rh-renin IC50 = 0.20 nM, hPRA IC50 = 19 nM).11,12

Figure 1.

Figure 1

Open in a new tab

Peptidomimetic DRIs, remikiren (1) and aliskiren (2).

Figure 2.

Figure 2

Open in a new tab

Nonpeptidomimetic DRIs and this study’s designed lead structure.

Although the oral bioavailability of aliskiren is low, the drug exhibits numerous clinical efficacies for hypertension and organ protection.15,16 Those results encouraged us to identify a ‘‘best-in-class” new-generation DRI with potent inhibitory activity against hPRA and a desirable pharmacokinetic profile for the control of hypertension. Thus, we aimed to discover structurally novel orally active DRIs, specifically nonpeptidomimetic compounds with a MW of <500 (generally expected to have good oral bioavailability) that demonstrate potent renin inhibitory activity.

In this paper, novel 2-carbamoyl morpholine derivatives were identified that exhibited not only the interactions with the two aspartate residues in the renin catalytic site but also novel interactions with the closed flap region in a different binding mode from previous DRIs. The optimization of the moieties that occupy the substrate S3 site and the nonsubstrate S3 subpocket (S3sp) was also performed to enhance the renin inhibitory activity using a structure-based drug design (SBDD) approach. As a result, compound 26 with a MW of <500 was identified as a highly potent and orally bioavailable DRI that occupied neither the S1′–S2′ sites nor the opened flap region used by other DRIs.

When designing the structurally novel DRIs, the focus was on the piperidine-based DRIs, such as 3–4 (Figure 2). In the X-ray structures of these compounds bound to renin (PDB 2BKT, 3G6Z),11,12 a protonated secondary amine of the piperidine ring forms two strong hydrogen bonds with two catalytically important aspartate residues of renin. Furthermore, each of these compounds binds to the “opened” form of renin, that is, the large substituent attached at the 4-position of the piperidine ring intrudes into a newly formed large pocket resulting from the rotation of the hairpin loop, commonly termed the “flap” ranging from the residues Thr72 to Ser81 of renin,13,14 and the N-benzylated tertiary amide of 4 extending from the 3-position of piperidine was designed as a novel pharmacophore tightly filling the hydrophobic S1–S3 sites, which the dialkoxyphenyl and isopropyl groups of 2 (PDB 2V0S) occupy. Meanwhile, the remaining hydrophilic substituent of 3 at the 5-position of the piperidine potentially extends into the S2′ site, which the 2,2-dimethylpropanamide part of 2 occupies.

On the basis of this X-ray information, we initially designed a simple cyclic secondary amine attached to N-cyclopropyl-N-[4-methoxy-3-(3-methoxypropoxy)benzyl]amide of the S1–S3 binding moiety (Figure 2; designed lead structure). In the designed compounds, the large substituent at the 4-position of the piperidine ring like 3–4 was not employed to reduce the MW and lipophilicity, while the substituent at the 5-position of the piperidine 3 was also not employed to reduce the MW and the number of HBDs and rotatable bonds. Instead of these substituents, it was necessary to discover novel interacting moieties that improve the renin inhibitory activity without significantly increasing the MW. Therefore, we evaluated synthetic compounds based on their inhibitory activity per MW, that is, the binding efficiency index [BEI = 1000 × (rh-renin pIC50)/MW].17

On the basis of our designed lead structure, a variety of simple cyclic secondary amines were investigated to form interactions with the two aspartate residues in the renin catalytic site. The inhibitory activities of the newly designed cyclic secondary amines 5–11 against rh-renin were measured via an enzyme immunoassay (EIA) or a fluorescence resonance energy transfer (FRET) assay (Table 1). Here, the piperidines 5–6, pyrrolidines 7–8, (2S)-morpholine 10, and piperazine 11 did not exhibit any interesting renin inhibitory activity. However, the (2R)-morpholine 9 exhibited moderate inhibitory activity against rh-renin (IC50 = 583 nM). While the inhibitory activity of 9 was clearly weaker than that of 2 (rh-renin IC50 = 0.7 nM), the BEI was comparable between the two (Table 2; 16.5 vs 16.6, respectively).

Table 1. Investigation of a Variety of Simple Cyclic Secondary Amines.

graphic file with name ml2c00280_0007.jpg

graphic file with name ml2c00280_0008.jpg

Open in a new tab
a

IC50 values are shown as the mean of duplicate measurements and calculated from the concentration–inhibition curve using Origin software (version 5.0, Microcal Software, Inc.).

Table 2. Investigation of the S3 Site Binding Moiety.

graphic file with name ml2c00280_0009.jpg

graphic file with name ml2c00280_0010.jpg

Open in a new tab
a

IC50 values are shown as the mean of duplicate measurements and calculated from the concentration–inhibition curve using Origin software (version 5.0, Microcal Software, Inc.).

b

IC50 values are shown as the mean of duplicate measurements and calculated from the concentration–inhibition curve using SAS software (version 9.1.3, SAS Institute Inc.).

c

Rahuel, J., et al. reported the IC50 values against rh-renin and hPRA were both 0.6 nM.9

To understand the binding mode of 9 and to determine the approaches for enhancing the renin inhibitory potency, X-ray crystallographic analysis was performed (Figure 3). As expected, the X-ray cocrystal structure of 9 bound to renin revealed that the compound 9 bound to the closed form of renin (PDB 7XGK), much like 2 (PDB 2V0S),9 while the protonated amine of the morpholine ring interacted with the two aspartate residues in the catalytic site of renin, and the methoxyphenyl group occupied the lipophilic S3 site, while the N-cyclopropyl group was located at the lipophilic S1 site. Meanwhile, native renin has a distinct narrow cavity commonly termed the S3sp, and the methoxypropyl side chain occupied this cavity. The introduction of the morpholine ring had a significant impact on the binding mode with renin; the oxygen atoms of the morpholine ring and the carbonyl group at 2-morpholine formed hydrogen bonds with the backbone NH groups of Ser76 and Thr77, respectively, on the flap in a closed conformation. These interactions were expected to contribute to the improvement of the renin inhibitory activity. The good BEI value and the novel binding mode of 9 encouraged the utilization of SBDD optimization using the X-ray cocrystal structure bound to renin.

Figure 3.

Figure 3

Open in a new tab

(A) X-ray cocrystal structure of aliskiren (2) bound to renin (PDB 2V0S). (B) X-ray cocrystal structure of 9 bound to renin (PDB 7XGK). The arrows and dashed lines indicate the hydrogen bonding interactions.

Next, a more preferable S3 site binding moiety, which could improve the van der Waals contact with the S3 boundaries, was investigated (Table 2). To this end, the methoxyphenyl moiety was replaced by a fused ring, such as benzofuran 12 or naphthalene 13, to enhance the interaction with the hydrophobic surface corresponding to the large S3 cavity. The naphthalene derivative 13 demonstrated an approximate 20-fold more potent renin inhibitory activity than 9. Because the renin inhibitory potency of 13 was significantly improved with a moderate increase in MW, the BEI value of 13 increased from that of 9 (18.9 vs 16.5, respectively).

To adjust the position of the methoxypropyl group binding to the S3sp, the naphthyl group was replaced by indole. Although the 1,6-indole derivative 14 just exhibited moderate renin inhibitory activity, the 1,3-indole derivative 15 exhibited greater inhibitory potency (15, rh-renin IC50 = 13 nM, vs 13, rh-renin IC50 = 30 nM) and a higher BEI value than 13 (15, 21.2, vs 13, 18.9). The hPRA IC50 of 15 was 84 nM, meaning the difference between the hPRA IC50 and rh-renin IC50 was relatively small compared with that of compounds 3 and 4 (>90-fold).

To investigate the possibility of renin inhibitory activity enhancement by introducing substituents to the indole ring of 15, a methyl substituent was investigated (Table 3). The introduction of a methyl group at the 2-, or 5-position of the indole was detrimental for the activity (16, 18), and at the 4-, 6-, or 7-position of the indole resulted in the maintenance of (19, 20) or a slight improvement to (17) the inhibitory potency. These results indicated that improving the inhibitory potency by introducing small substituents to the indole ring would prove to be problematic considering BEI; thus, the optimization of the S3sp binding moiety was initiated.

Table 3. Introducing a Methyl Substituent to the Indole Ring.

graphic file with name ml2c00280_0011.jpg

compd R1 R2 R3 R4 R5 rh-renin IC50 (FRET, nM)a hPRA IC50 (nM)b MW ClogP BEI
15 H H H H H 13 84 371.5 2.30 21.2
16 Me H H H H >10000   385.5 2.75  
17 H Me H H H 5.8 54 385.5 2.80 21.3
18 H H Me H H 274   385.5 2.80 17.0
19 H H H Me H 19 74 385.5 2.80 20.0
20 H H H H Me 9.3 103 385.5 2.80 20.8
Open in a new tab
a

IC50 values are shown as the mean of duplicate measurements and calculated from the concentration–inhibition curve using Origin software (version 5.0, Microcal Software, Inc.).

b

IC50 values are shown as the mean of duplicate measurements and calculated from the concentration–inhibition curve using SAS software (version 9.1.3, SAS Institute Inc.).

The methoxypropyl side chain is a well-known motif for binding to the renin S3sp. The ether oxygen of the methoxypropyl group forms a hydrogen bond with the backbone NH group of Tyr14 at the bottom of the channel.18 Here, a more preferable S3sp binding chain was investigated to adjust the position of the hydrogen bond acceptor (HBA) for interaction with the NH group of Tyr14 (Table 4). When comparing 22 and 23 with 21 (a racemate of 15), the replacement of a three-methylene linker by a four-methylene linker was found to improve the renin inhibitory potency, presumably because the four-methylene-linker suitably positioned the oxygen to interact with the NH group of Tyr14, while the incorporation of an ester functionality into the four-methylene-linker slightly weakened the inhibitory potency (24 vs 23). Meanwhile, researchers at Vitae Pharmaceuticals demonstrated that the terminus of the chain occupying the S3sp could be substituted with methyl carbamate and that its suitably positioned hydrogen bond acceptor and donor could interact with not only the NH group of Tyr14 but also the carbonyl group of Gly217.18 With reference to the above information, replacing the α-positioned methylene of the ester by the carbamate NH group was conducted, and the change actually led to an enhancement of the inhibitory potency (25 vs 24). As a result of the optimization, compound 26, an enantiomer of 25, exhibited a 14-fold more potent inhibitory activity against rh-renin and was 47-fold more potent against hPRA compared with 15. The greater enhancement of the hPRA inhibition than the rh-renin inhibition might be attributed to a lowering of the PPB due to the reduced lipophilicity (ClogP, 2.18 for 26, vs 2.30 for 15). In the X-ray cocrystal structure of 26 bound to renin (Figure 4, PDB 7XGO), the carbamate NH group formed a hydrogen bond with the carbonyl oxygen of Gly217, as expected, while the carbonyl oxygen of the carbamate formed a hydrogen bond with the backbone NH group of Tyr14.

Table 4. Optimization of the S3sp Binding Chain.

graphic file with name ml2c00280_0015.jpg

compd R * rh-renin IC50 (FRET, nM)a hPRA IC50 (nM)b MW ClogP BEI
15 (CH2)3OMe (R) 13 84 371.5 2.30 21.2
21 (CH2)3OMe (RS) 23   371.5 2.30 20.6
22 (CH2)2OMe (RS) 103   357.5 2.00 19.5
23 (CH2)4OMe (RS) 4.3   385.5 2.39 21.7
24 (CH2)4CO2Me (RS) 10   413.5 2.62 19.3
25 (CH2)3NHCO2Me (RS) 1.4   414.5 2.18 21.4
26 (CH2)3NHCO2Me (R) 0.9 1.8 414.5 2.18 21.8
Open in a new tab
a

IC50 values are shown as the mean of duplicate measurements, and calculated from the concentration–inhibition curve using Origin software (version 5.0, Microcal Software, Inc.).

b

IC50 values are shown as the mean of duplicate measurements, and calculated from the concentration–inhibition curve using SAS software (version 9.1.3, SAS Institute Inc.).

Figure 4.

Figure 4

Open in a new tab

X-ray cocrystal structure of 26 bound to renin (PDB 7XGO). The dashed lines indicate the hydrogen bonding interactions.

Compound 26 exhibited a high BEI value (21.8) and potent inhibitory activity against hPRA (IC50 = 1.8 nM) compared with aliskiren (2) (BEI, 16.6, hPRA IC50 = 2.5 nM). Therefore, the antihypertensive efficacy of 26 was investigated by using double transgenic mice (Tsukuba hypertensive mice [THM]), carrying both the human angiotensinogen and the human renin gene (Figure 5).19,20 In this model, 2 has been reported to be effective at 10 mg/kg (po),21 and 26 also demonstrated a significantly potent hypotensive effect at 10 mg/kg (po). In contrast to 2, compound 26 possessed drug-like physicochemical characteristics that are regarded as important predictors of oral bioavailability, such as the MW (26, 414.5, vs 2, 551.8), the ClogP (26, 2.18, vs 2, 3.51), the number of HBDs (26, 2, vs 2, 6), the number of HBAs (26, 8, vs 2, 9), the number of rotatable bonds (26, 9, vs 2, 19), and the topological polar surface area (TPSA: 26, 82 Å2, vs 2, 146 Å2). Lipinski’s Rule-of-Five alerted that molecules with poor oral bioavailability have two or more of the following characteristics: MW > 500, ClogP > 5, HBDs > 5, and HBAs > 10,22 and Veber et al. proposed the two criteria to meet good oral bioavailability: (1) ≤10 rotatable bonds and (2) polar surface area ≤140 Å2.23 Compound 26, however, presented various pharmacokinetic issues, including metabolic instability (human microsome CLint, 90 μL/min/mg) and time dependent inhibition (TDI) of CYP3A4 (Kobs, 374 × 10–4/min). Therefore, further optimization studies were planned to overcome the drawbacks and to improve the antihypertensive potency, and its results will be reported in due course.

Figure 5.

Figure 5

Open in a new tab

Hypotensive effect of 26 on Tsukuba hypertensive mice. Data shown as mean values ± SEM. A statistical analysis was performed using two-way ANOVA followed by Bonferroni’s multiple comparison test. **P < 0.01 vs vehicle-treated mice.

The synthesis of 26 is depicted in Scheme 1. Here, the reductive amination of 1H-indole-3-carbaldehyde (27) with cyclopropylamine, followed by BOC protection and alkylation using N-3-bromoethyl-phthalimide, produced compound 28. Following this, the phthalimide of 28 was cleaved using hydrazine prior to carbamoylation using methyl chloroformate and subsequent BOC deprotection, giving 29. Finally, the amine 29 was condensed with (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (30), followed by removal of the BOC group, to obtain the desired compound 26.

Scheme 1. Synthesis of Compound 26.

Scheme 1

Open in a new tab

Reagents and conditions: (a) c-PrNH2, EtOH, 50 °C, NaBH4, EtOH, rt, (Boc)2O, Et3N, CHCl3, rt, 81% for 3 steps; (b) N-(3-bromopropyl)phthalimide, NaH, DMF, rt, 84%; (c) H2NNH2·H2O, 40 °C, EtOH, 56%; (d) methyl chloroformate, Et3N, CHCl3, 0 °C, 86%; (e) TMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 64%; (f) (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (30), EDCI·HCl, HOBt, DMF, rt; (g) TMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 39% for 2 steps.

In summary, 2-carbamoyl morpholine was identified as a novel scaffold of DRIs. The scaffold exhibited novel hydrogen-bonding interactions with the closed flap region as well as interactions with the two aspartate residues in the renin catalytic site. Thus, the derivatives based on the scaffold exhibited potent renin inhibitory activity with no occupation of either the S1′–S2′ sites or the opened flap region used by other DRIs. As a result of the optimization using the BEI as a benchmark from the lead compound 9 (BEI: 16.5), compound 26 (BEI: 21.8) with a MW of <500 was identified; this compound demonstrated highly potent hPRA inhibition comparable to aliskiren (2; BEI: 16.6). Even though the MW of 26 was lower than that of 2, compound 26 efficiently formed hydrophobic interactions and six hydrogen bonds with renin. Furthermore, the compound demonstrated potent in vivo antihypertensive efficacy via oral administration in THM. However, the compound did present certain issues that need to be addressed, including metabolic instability and CYP3A4 inhibitory activity. Further optimization studies aimed at overcoming the drawbacks of 26, leading to the discovery of the clinical candidate SPH3127, and its results will be reported in due course.

Acknowledgments

We thank Dr. Kazumi Ikeda and Norihiko Iwazaki for the pharmacokinetic data.

Glossary

Abbreviations

BEI

binding efficiency index

DRI

direct renin inhibitor

EIA

enzyme immunoassay

hPRA

human plasma renin activity

RAAS

renin–angiotensin–aldosterone system

rh-renin

recombinant human renin

SBDD

structure-based drug design

SBP

systolic blood pressure

TDI

time dependent inhibition

THM

Tsukuba hypertensive mice

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00280.

  • 1H NMR spectra for the biologically assayed compounds, 13C NMR spectra for 9, 15, and 26, HPLC trace for 26, synthetic procedure for compounds 5–26, biological assay protocols, X-ray crystallographic information for the renin–inhibitor complexes, and calculation of physicochemical properties (PDF)

  • Molecular formula strings (XLSX)

Author Contributions

D.I., H.S., N.A., Y.T., Y.T., T.T., J.X., J.S., Y.K., H.A., T.K., G.X. and T.I. contributed the design and synthesis of compounds; K.T. and A.K. contributed the X-ray crystallography; M.N., Y.I. and H.Y. contributed the in vitro and in vivo pharmacological studies.

The authors declare the following competing financial interest(s): D.I., H.S., N.A., Y.T., Y.T., T.T., H.A., T.K., K.T., A.K., M.N., Y.I., H.Y. and T.I. were employed by Mitsubishi Tanabe Pharma Corporation at the time this work was done; J.X., J.S., Y.K. and G.X. were employed by Shanghai Pharmaceuticals Holding Co., Ltd. at the time this work was done.

Supplementary Material

ml2c00280_si_001.pdf (1.9MB, pdf)
ml2c00280_si_002.xlsx (10.7KB, xlsx)

References

  1. Whelton P. K.; Carey R. M.; Aronow W. S.; Casey D. E.; Collins K. J.; Dennison-Himmelfarb C.; DePalma S. M.; Gidding S.; Jamerson K. A.; Jones D. W.; MacLaughlin E. J.; Muntner P.; Ovbiagele B.; Smith S. C.; Spencer C. C.; Stafford R. S.; Taler S. J.; Thomas R. J.; Williams K. A.; Williamson J. D.; Wright J. T. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018, 71, e13–e115. 10.1161/HYP.0000000000000065. [DOI] [PubMed] [Google Scholar]
  2. Weber M. A.; Giles T. D. Inhibiting the renin-angiotensin system to prevent cardiovascular diseases: do we need a more comprehensive strategy?. Rev. Cardiovasc. Med. 2006, 7, 45–54. [PubMed] [Google Scholar]
  3. Azizi M.; Webb R.; Nussberger J.; Hollenberg N. K. Renin inhibition with aliskiren: where are we now, and where are we going?. J. Hypertens. 2006, 24, 243–256. 10.1097/01.hjh.0000202812.72341.99. [DOI] [PubMed] [Google Scholar]
  4. Webb R. L.; Schiering N.; Sedrani R.; Maibaum J. Direct renin inhibitors as a new therapy for hypertension. J. Med. Chem. 2010, 53, 7490–7520. 10.1021/jm901885s. [DOI] [PubMed] [Google Scholar]
  5. Yokokawa F.; Maibaum J. Recent advances in the discovery of non-peptidic direct renin inhibitors as antihypertensives: new patent applications in years 2000 – 2008. Expert Opin. Ther. Patents 2008, 18, 581–602. 10.1517/13543776.18.6.581. [DOI] [Google Scholar]
  6. Yokokawa F. Recent progress on the discovery of non-peptidic direct renin inhibitors for the clinical management of hypertension. Expert Opin. Drug Discovery 2013, 8, 673–690. 10.1517/17460441.2013.791279. [DOI] [PubMed] [Google Scholar]
  7. Tong L.; Pav S.; Lamarre D.; Pilote L.; LaPlante S.; Anderson P. C.; Jung G. High resolution crystal structures of recombinant human renin in complex with polyhydroxymonoamide inhibitors. J. Mol. Biol. 1995, 250, 211–222. 10.1006/jmbi.1995.0372. [DOI] [PubMed] [Google Scholar]
  8. Kleinbloesem C. H.; Weber C.; Fahrner E.; Dellenbach M.; Welker H.; Schröter V.; Beiz G. G. Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects. Clin. Pharmacol. Ther. 1993, 53, 585–592. 10.1038/clpt.1993.74. [DOI] [PubMed] [Google Scholar]
  9. Rahuel J.; Rasetti V.; Maibaum J.; Rüeger H.; Göschke R.; Cohen N. C.; Stutz S.; Cumin F.; Fuhrer W.; Wood J. M.; Grütter M. G. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem. Biol. 2000, 7, 493–504. 10.1016/S1074-5521(00)00134-4. [DOI] [PubMed] [Google Scholar]
  10. Vaidyanathan S.; Jarugula V.; Dieterich H. A.; Howard D.; Dole W. P. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin. Pharmacokinet. 2008, 47, 515–531. 10.2165/00003088-200847080-00002. [DOI] [PubMed] [Google Scholar]
  11. Märki H. P.; Binggeli A.; Bittner B.; Bohner-Lang V.; Breu V.; Bur D.; Coassolo P. H.; Clozel J. P.; D’Arcy A.; Doebeli H.; Fischli W.; Funk C. H.; Foricher J.; Giller T.; Grüninger F.; Guenzi A.; Güller R.; Hartung T.; Hirth G.; Jenny C. H.; Kansy M.; Klinkhammer U.; Lave T.; Lohri B.; Luft F. C.; Mervaala E. M.; Müller D. N.; Müller M.; Montavon F.; Oefner C. H.; Qiu C.; Reichel A.; Sanwald-Ducray P.; Scalone M.; Schleimer M.; Schmid R.; Stadler H.; Treiber A.; Valdenaire O.; Vieira E.; Waldmeier P.; Wiegand-Chou R.; Wilhelm M.; Wostl W.; Zell M.; Zell R. Piperidine renin inhibitors: from leads to drug candidates. Il Farmaco 2001, 56, 21–27. 10.1016/S0014-827X(01)01004-7. [DOI] [PubMed] [Google Scholar]
  12. Bezençon O.; Bur D.; Weller T.; Richard-Bildstein S.; Remen L.; Sifferlen T.; Corminboeuf O.; Grisostomi C.; Boss C.; Prade L.; Delahaye S.; Treiber A.; Strickner P.; Binkert C.; Hess P.; Steiner B.; Fischli W. Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors. J. Med. Chem. 2009, 52, 3689–3702. 10.1021/jm900022f. [DOI] [PubMed] [Google Scholar]
  13. Oefner C.; Binggeli A.; Breu V.; Bur D.; Clozel J. P.; D’Arcy A.; Dorn A.; Fischli W.; Grüninger F.; Güller R.; Hirth G.; Märki H.; Mathews S.; Müller M.; Ridley R. G.; Stadier H.; Vieira E.; Wilhelm M.; Winkler F.; Wostl W. Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases. Chem. Biol. 1999, 6, 127–131. 10.1016/S1074-5521(99)89004-8. [DOI] [PubMed] [Google Scholar]
  14. Vieira E.; Binggeli A.; Breu V.; Bur D.; Fischli W.; Güller R.; Hirth G.; Märki H. P.; Müller M.; Oefner C.; Scalone M.; Stadler H.; Wihelm M.; Wostl W. Substituted piperidines—highly potent renin inhibitors due to induced fit adaptation of the active site. Bioorg. Med. Chem. Lett. 1999, 9, 1397–1402. 10.1016/S0960-894X(99)00195-X. [DOI] [PubMed] [Google Scholar]
  15. Oparil S.; Yarows S. A.; Patel S.; Fang H.; Zhang J.; Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007, 370, 221–229. 10.1016/S0140-6736(07)61124-6. [DOI] [PubMed] [Google Scholar]
  16. Parving H. H.; Persson F.; Lewis J. B.; Lewis E. J.; Hollenberg N. K. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N. Engl. J. Med. 2008, 358, 2433–2446. 10.1056/NEJMoa0708379. [DOI] [PubMed] [Google Scholar]
  17. Abad-Zapatero C.; Metz J. T. Ligand efficiency indices as guideposts for drug discovery. Drug Discovery Today 2005, 10, 464–469. 10.1016/S1359-6446(05)03386-6. [DOI] [PubMed] [Google Scholar]
  18. Xu Z.; Cacatian S.; Yuan J.; Simpson R. D.; Jia L.; Zhao W.; Tice C. M.; Flaherty P. T.; Guo J.; Ishchenko A.; Singh S. B.; Wu Z.; McKeever B. M.; Scott B. B.; Bukhtiyarov Y.; Berbaum J.; Mason J.; Panemangalore R.; Cappiello M. G.; Bentley R.; Doe C. P.; Harrison R. K.; McGeehan G. M.; Dillard L. W.; Baldwin J. J.; Claremon D. A. Optimization of orally bioavailable alkyl amine renin inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 694–699. 10.1016/j.bmcl.2009.11.066. [DOI] [PubMed] [Google Scholar]
  19. Fukamizu A.; Sugimura K.; Takimoto E.; Sugiyama F.; Seo M. S.; Takahashi S.; Hatae T.; Kajiwara N.; Yagami K.; Murakami K. Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J. Biol. Chem. 1993, 268, 11617–11621. 10.1016/S0021-9258(19)50246-0. [DOI] [PubMed] [Google Scholar]
  20. Shimokama T.; Haraoka S.; Horiguchi H.; Sugiyama F.; Murakami K.; Watanabe T. The Tsukuba hypertensive mouse (transgenic mouse carrying human genes for both renin and angiotensinogen) as a model of human malignant hypertension: development of lesions and morphometric analysis. Virchows Archiv 1998, 432, 169–175. 10.1007/s004280050152. [DOI] [PubMed] [Google Scholar]
  21. Sun X.; Wen X.; Chen Y. Y.; Shi C.; Gao C.; Wu Y.; Wang L. J.; Yang X. H.; Sun H. Discovery of highly potent renin inhibitors potentially interacting with the S3′ subsite of renin. Eur. J. Med. Chem. 2015, 103, 269–288. 10.1016/j.ejmech.2015.08.060. [DOI] [PubMed] [Google Scholar]
  22. Lipinski C. A.; Lombardo F.; Dominy B. W.; Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3–25. 10.1016/S0169-409X(96)00423-1. [DOI] [PubMed] [Google Scholar]
  23. Veber D. F.; Johnson S. R.; Cheng H.-Y.; Smith B. R.; Ward K. W.; Kopple K. D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615–2623. 10.1021/jm020017n. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml2c00280_si_001.pdf (1.9MB, pdf)
ml2c00280_si_002.xlsx (10.7KB, xlsx)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES