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Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin.

Rahuel J, Rasetti V, Maibaum J, Rüeger H, Göschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grütter MG
Chem Biol 7 493-504 (2000)
Related entries: 1rne, 2v0z, 2v10, 2v11, 2v12, 2v16

Cited: 145 times
EuropePMC logo PMID: 10903938

Abstract

Background

The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin.

Results

Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised.

Conclusion

Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.

Reviews citing this publication (56)

  1. Renin inhibition with aliskiren: where are we now, and where are we going? Azizi M, Webb R, Nussberger J, Hollenberg NK. J. Hypertens. 24 243-256 (2006)
  2. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Cooper SA, Whaley-Connell A, Habibi J, Wei Y, Lastra G, Manrique C, Stas S, Sowers JR. Am. J. Physiol. Heart Circ. Physiol. 293 H2009-23 (2007)
  3. Structure-based drug screening for G-protein-coupled receptors. Shoichet BK, Kobilka BK. Trends Pharmacol. Sci. 33 268-272 (2012)
  4. Renin inhibition: what are the therapeutic opportunities? Fisher ND, Hollenberg NK. J Am Soc Nephrol 16 592-599 (2005)
  5. In silico pharmacology for drug discovery: applications to targets and beyond. Ekins S, Mestres J, Testa B. Br. J. Pharmacol. 152 21-37 (2007)
  6. Aliskiren: the first renin inhibitor for clinical treatment. Jensen C, Herold P, Brunner HR. Nat Rev Drug Discov 7 399-410 (2008)
  7. Direct renin inhibition with aliskiren in hypertension and target organ damage. Müller DN, Luft FC. Clin J Am Soc Nephrol 1 221-228 (2006)
  8. Angiotensin-(1-7): pharmacological properties and pharmacotherapeutic perspectives. Iusuf D, Henning RH, van Gilst WH, Roks AJ. Eur. J. Pharmacol. 585 303-312 (2008)
  9. Renin inhibition in hypertension. Gradman AH, Kad R. J. Am. Coll. Cardiol. 51 519-528 (2008)
  10. New pharmacological treatments for improving renal outcomes in diabetes. Declèves AE, Sharma K. Nat Rev Nephrol 6 371-380 (2010)
  11. The genesis of high-throughput structure-based drug discovery using protein crystallography. Kuhn P, Wilson K, Patch MG, Stevens RC. Curr Opin Chem Biol 6 704-710 (2002)
  12. The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Verdecchia P, Angeli F, Mazzotta G, Gentile G, Reboldi G. Vasc Health Risk Manag 4 971-981 (2008)
  13. Is there a future for renin inhibitors? Fisher ND, Hollenberg NK. Expert Opin Investig Drugs 10 417-426 (2001)
  14. Beta-secretase as a target for Alzheimer's disease drug discovery: an overview of in vitro methods for characterization of inhibitors. Mancini F, De Simone A, Andrisano V. Anal Bioanal Chem 400 1979-1996 (2011)
  15. Potential of renin inhibition in cardiovascular disease. Stanton A. J Renin Angiotensin Aldosterone Syst 4 6-10 (2003)
  16. Therapeutic potential of renin inhibitors in the management of cardiovascular disorders. Stanton A. Am J Cardiovasc Drugs 3 389-394 (2003)
  17. Renin-angiotensin-aldosterone system blockade effects on the kidney in the elderly: benefits and limitations. Turgut F, Balogun RA, Abdel-Rahman EM. Clin J Am Soc Nephrol 5 1330-1339 (2010)
  18. An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. Aulakh GK, Sodhi RK, Singh M. Life Sci. 81 615-639 (2007)
  19. New roles for renin and prorenin in heart failure and cardiorenal crosstalk. Schroten NF, Gaillard CA, van Veldhuisen DJ, Szymanski MK, Hillege HL, de Boer RA. Heart Fail Rev 17 191-201 (2012)
  20. A fully integrated protein crystallization platform for small-molecule drug discovery. Hosfield D, Palan J, Hilgers M, Scheibe D, McRee DE, Stevens RC. J. Struct. Biol. 142 207-217 (2003)
  21. Aliskiren: a novel renoprotective agent or simply an alternative to ACE inhibitors? Wiggins KJ, Kelly DJ. Kidney Int. 76 23-31 (2009)
  22. Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge. Cohen NC. Chem Biol Drug Des 70 557-565 (2007)
  23. Direct inhibition of renin as a cardiovascular pharmacotherapy: focus on aliskiren. Sepehrdad R, Frishman WH, Stier CT, Sica DA. Cardiol Rev 15 242-256 (2007)
  24. Renin inhibition. Azizi M. Curr. Opin. Nephrol. Hypertens. 15 505-510 (2006)
  25. Blocking the RAAS at different levels: an update on the use of the direct renin inhibitors alone and in combination. Cagnoni F, Njwe CA, Zaninelli A, Ricci AR, Daffra D, D'Ospina A, Preti P, Destro M. Vasc Health Risk Manag 6 549-559 (2010)
  26. The role of medical structural genomics in discovering new drugs for infectious diseases. Van Voorhis WC, Hol WG, Myler PJ, Stewart LJ. PLoS Comput. Biol. 5 e1000530 (2009)
  27. Direct renin inhibition: clinical pharmacology. Azizi M. J. Mol. Med. 86 647-654 (2008)
  28. Renin inhibitors, clinical experience. Westermann D, Schmieder R, Schultheiss HP, Tschöpe C. J. Mol. Med. 86 691-695 (2008)
  29. Renin inhibitors and cardiovascular and renal protection: an endless quest? Azizi M, Ménard J. Cardiovasc Drugs Ther 27 145-153 (2013)
  30. Aliskiren: a renin inhibitor offering a new approach for the treatment of hypertension. O'Brien E. Expert Opin Investig Drugs 15 1269-1277 (2006)
  31. Now that we have a direct renin inhibitor, what should we do with it? Stanton A. Curr. Hypertens. Rep. 10 194-200 (2008)
  32. Probes for chemical genomics by design. Zanders ED, Bailey DS, Dean PM. Drug Discov. Today 7 711-718 (2002)
  33. Pharmaceutical R&D in the spotlight: why is there still unmet medical need? Schmid EF, Smith DA. Drug Discov. Today 12 998-1006 (2007)
  34. A molecular informatics view on best practice in multi-parameter compound optimization. Lusher SJ, McGuire R, Azevedo R, Boiten JW, van Schaik RC, de Vlieg J. Drug Discov. Today 16 555-568 (2011)
  35. Peptides as receptor ligand drugs and their relationship to G-coupled signal transduction. Mizejewski GJ. Expert Opin Investig Drugs 10 1063-1073 (2001)
  36. Pharmacokinetic, pharmacodynamic and clinical evaluation of aliskiren for hypertension treatment. Reboldi G, Gentile G, Angeli F, Verdecchia P. Expert Opin Drug Metab Toxicol 7 115-128 (2011)
  37. Potential of RAS inhibition to improve metabolic bone disorders. Gebru Y, Diao TY, Pan H, Mukwaya E, Zhang Y. Biomed Res Int 2013 932691 (2013)
  38. Rationale for combining blockers of the renin-angiotensin system. Azizi M, Wuerzner G. Semin. Nephrol. 27 544-554 (2007)
  39. Direct renin inhibition: an analysis of possible benefits. Dockery BK, Bisognano JD. Curr. Hypertens. Rep. 10 313-318 (2008)
  40. Reducing cardiovascular events and end-organ damage in patients with hypertension: new considerations. Harmon L, Chilton RJ, Spellman C. Postgrad Med 123 7-17 (2011)
  41. Renin Inhibition with Aliskiren: A Decade of Clinical Experience. Pantzaris ND, Karanikolas E, Tsiotsios K, Velissaris D. J Clin Med 6 (2017)
  42. The development of the direct renin inhibitor aliskiren: treating hypertension and beyond. Siragy H, Huang J, Lieb DC. Expert Opin Emerg Drugs 13 417-430 (2008)
  43. Aliskiren: clinical experience and future perspectives of renin inhibition. Sureshkumar KK, Vasudevan S, Marcus RJ, Hussain SM, McGill RL. Expert Opin Pharmacother 9 825-837 (2008)
  44. Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations. Rich DH, Bursavich MG, Estiarte MA. Biopolymers 66 115-125 (2002)
  45. The Renin Report. Sica DA, Ichihara A. J Renin Angiotensin Aldosterone Syst 7 247-251 (2006)
  46. Update on newer antihypertensive medicines and interventions. Wu KC, Gerstenblith G. J. Cardiovasc. Pharmacol. Ther. 15 257-267 (2010)
  47. Aliskiren as a novel therapeutic agent for hypertension and cardio-renal diseases. Rashikh A, Ahmad SJ, Pillai KK, Najmi AK. J. Pharm. Pharmacol. 64 470-481 (2012)
  48. On target to dual block RAS? Papadopoulos DP, Papademetriou V, Makris TK. Angiology 60 739-749 (2009)
  49. [Advantages and limitations of renin inhibition with aliskiren]. Azizi M, Frank M, Steichen O, Blanchard A. Ann Pharm Fr 69 142-150 (2011)
  50. Amaranth as a Source of Antihypertensive Peptides. Nardo AE, Suárez S, Quiroga AV, Añón MC. Front Plant Sci 11 578631 (2020)
  51. Computational anti-COVID-19 drug design: progress and challenges. Wang J, Zhang Y, Nie W, Luo Y, Deng L. Brief Bioinform 23 bbab484 (2022)
  52. Inhibition of renin and the (pro)renin receptor system. Guang C, Jiang B, Phillips RD, Milani F. Blood Press. 21 377-385 (2012)
  53. Sequence, Structural Analysis and Metrics to Define the Unique Dynamic Features of the Flap Regions Among Aspartic Proteases. McGillewie L, Ramesh M, Soliman ME. Protein J. 36 385-396 (2017)
  54. Therapeutic Implications of Renin-Angiotensin System Modulators in Alzheimer's Dementia. Ababei DC, Bild V, Macadan I, Vasincu A, Rusu RN, Blaj M, Stanciu GD, Lefter RM, Bild W. Pharmaceutics 15 2290 (2023)
  55. [Molecular modeling in the battle against AIDS. Drugs design in the development of substrate-like HIV protease inhibitors] Klebe G. Pharm Unserer Zeit 30 194-201 (2001)
  56. [The pharmacological profile and clinical findings on aliskiren (Rasilez tablet), direct renin inhibitor]. Tanaka M, Akahori M, Goto H. Nippon Yakurigaku Zasshi 135 159-168 (2010)

Articles citing this publication (89)

  1. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Circulation 111 1012-1018 (2005)
  2. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Wood JM, Maibaum J, Rahuel J, Grütter MG, Cohen NC, Rasetti V, Rüger H, Göschke R, Stutz S, Fuhrer W, Schilling W, Rigollier P, Yamaguchi Y, Cumin F, Baum HP, Schnell CR, Herold P, Mah R, Jensen C, O'Brien E, Stanton A, Bedigian MP. Biochem. Biophys. Res. Commun. 308 698-705 (2003)
  3. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Stanton A, Jensen C, Nussberger J, O'Brien E. Hypertension 42 1137-1143 (2003)
  4. Fragment-based identification of druggable 'hot spots' of proteins using Fourier domain correlation techniques. Brenke R, Kozakov D, Chuang GY, Beglov D, Hall D, Landon MR, Mattos C, Vajda S. Bioinformatics 25 621-627 (2009)
  5. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. O'Brien E, Barton J, Nussberger J, Mulcahy D, Jensen C, Dicker P, Stanton A. Hypertension 49 276-284 (2007)
  6. The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins. Kozakov D, Grove LE, Hall DR, Bohnuud T, Mottarella SE, Luo L, Xia B, Beglov D, Vajda S. Nat Protoc 10 733-755 (2015)
  7. Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats. Wood JM, Schnell CR, Cumin F, Menard J, Webb RL. J. Hypertens. 23 417-426 (2005)
  8. Apo and inhibitor complex structures of BACE (beta-secretase). Patel S, Vuillard L, Cleasby A, Murray CW, Yon J. J. Mol. Biol. 343 407-416 (2004)
  9. Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. Lastra G, Habibi J, Whaley-Connell AT, Manrique C, Hayden MR, Rehmer J, Patel K, Ferrario C, Sowers JR. Endocrinology 150 2561-2568 (2009)
  10. Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Kushiro T, Itakura H, Abo Y, Gotou H, Terao S, Keefe DL. Hypertens. Res. 29 997-1005 (2006)
  11. Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren. Vaidyanathan S, Camenisch G, Schuetz H, Reynolds C, Yeh CM, Bizot MN, Dieterich HA, Howard D, Dole WP. J Clin Pharmacol 48 1323-1338 (2008)
  12. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers. Vaidyanathan S, Valencia J, Kemp C, Zhao C, Yeh CM, Bizot MN, Denouel J, Dieterich HA, Dole WP. Int. J. Clin. Pract. 60 1343-1356 (2006)
  13. Functional plasticity in the substrate binding site of beta-secretase. Gorfe AA, Caflisch A. Structure 13 1487-1498 (2005)
  14. DEEPScreen: high performance drug-target interaction prediction with convolutional neural networks using 2-D structural compound representations. Rifaioglu AS, Nalbat E, Atalay V, Martin MJ, Cetin-Atalay R, Doğan T. Chem Sci 11 2531-2557 (2020)
  15. Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat. Habibi J, Whaley-Connell A, Hayden MR, DeMarco VG, Schneider R, Sowers SD, Karuparthi P, Ferrario CM, Sowers JR. Endocrinology 149 5643-5653 (2008)
  16. Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat. Whaley-Connell A, Habibi J, Cooper SA, Demarco VG, Hayden MR, Stump CS, Link D, Ferrario CM, Sowers JR. Am. J. Physiol. Endocrinol. Metab. 295 E103-9 (2008)
  17. Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects. Vaidyanathan S, Reynolds C, Yeh CM, Bizot MN, Dieterich HA, Howard D, Dole WP. J Clin Pharmacol 47 453-460 (2007)
  18. Aliskiren binds to renin and prorenin bound to (pro)renin receptor in vitro. Biswas KB, Nabi AH, Arai Y, Nakagawa T, Ebihara A, Ichihara A, Watanabe T, Inagami T, Suzuki F. Hypertens. Res. 33 1053-1059 (2010)
  19. Potential virtual lead identification in the discovery of renin inhibitors: application of ligand and structure-based pharmacophore modeling approaches. Thangapandian S, John S, Sakkiah S, Lee KW. Eur J Med Chem 46 2469-2476 (2011)
  20. Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B. J. Mol. Biol. 355 249-261 (2006)
  21. Ensemble-docking approach on BACE-1: pharmacophore perception and guidelines for drug design. Limongelli V, Marinelli L, Cosconati S, Braun HA, Schmidt B, Novellino E. ChemMedChem 2 667-678 (2007)
  22. Evaluating molecular mechanism of hypotensive peptides interactions with renin and angiotensin converting enzyme. He R, Aluko RE, Ju XR. PLoS ONE 9 e91051 (2014)
  23. Highly sensitive intramolecularly quenched fluorogenic substrates for renin based on the combination of L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid with 2,4-dinitrophenyl groups at various positions. Paschalidou K, Neumann U, Gerhartz B, Tzougraki C. Biochem. J. 382 1031-1038 (2004)
  24. Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome. Hayden MR, Sowers JR. J Am Soc Hypertens 2 239-266 (2008)
  25. Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases. Politi A, Durdagi S, Moutevelis-Minakakis P, Kokotos G, Papadopoulos MG, Mavromoustakos T. Eur J Med Chem 44 3703-3711 (2009)
  26. The proprotein convertase subtilisin/kexin type 9 (PCSK9) active site and cleavage sequence differentially regulate protein secretion from proteolysis. Chorba JS, Shokat KM. J. Biol. Chem. 289 29030-29043 (2014)
  27. Aliskiren reduces prorenin receptor expression and activity in cultured human aortic smooth muscle cells. Ferri N, Greco CM, Maiocchi G, Corsini A. J Renin Angiotensin Aldosterone Syst 12 469-474 (2011)
  28. Creating carbon-carbon bonds with samarium diiodide for the synthesis of modified amino acids and peptides. Ebran JP, Jensen CM, Johannesen SA, Karaffa J, Lindsay KB, Taaning R, Skrydstrup T. Org. Biomol. Chem. 4 3553-3564 (2006)
  29. Renin inhibition reverses renal disease in transgenic mice by shifting the balance between profibrotic and antifibrotic agents. Kavvadas P, Weis L, Abed AB, Feldman DL, Dussaule JC, Chatziantoniou C. Hypertension 61 901-907 (2013)
  30. Design and optimization of renin inhibitors: Orally bioavailable alkyl amines. Tice CM, Xu Z, Yuan J, Simpson RD, Cacatian ST, Flaherty PT, Zhao W, Guo J, Ishchenko A, Singh SB, Wu Z, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Müller D, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA. Bioorg. Med. Chem. Lett. 19 3541-3545 (2009)
  31. Dietary sodium intake modulates renal excretory responses to intrarenal angiotensin (1-7) administration in anesthetized rats. O'Neill J, Corbett A, Johns EJ. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304 R260-6 (2013)
  32. Renin inhibition with aliskiren. Wuerzner G, Azizi M. Clin. Exp. Pharmacol. Physiol. 35 426-430 (2008)
  33. Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors. Machauer R, Veenstra S, Rondeau JM, Tintelnot-Blomley M, Betschart C, Neumann U, Paganetti P. Bioorg. Med. Chem. Lett. 19 1361-1365 (2009)
  34. The discovery and preparation of disubstituted novel amino-aryl-piperidine-based renin inhibitors. Cody WL, Holsworth DD, Powell NA, Jalaie M, Zhang E, Wang W, Samas B, Bryant J, Ostroski R, Ryan MJ, Edmunds JJ. Bioorg. Med. Chem. 13 59-68 (2005)
  35. Picomolar Inhibition of Plasmepsin V, an Essential Malaria Protease, Achieved Exploiting the Prime Region. Gambini L, Rizzi L, Pedretti A, Taglialatela-Scafati O, Carucci M, Pancotti A, Galli C, Read M, Giurisato E, Romeo S, Russo I. PLoS ONE 10 e0142509 (2015)
  36. Size of the aliphatic chain of sodium houttuyfonate analogs determines their affinity for renin and angiotensin I converting enzyme. Yuan L, Wu J, Aluko RE. Int. J. Biol. Macromol. 41 274-280 (2007)
  37. Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents. Sandgren V, Bäck M, Kvarnström I, Dahlgren A. Open Med Chem J 7 1-15 (2013)
  38. The role of direct renin inhibitors in the treatment of the hypertensive diabetic patient. Riccioni G. Ther Adv Endocrinol Metab 4 139-145 (2013)
  39. Role of aliskiren in blood pressure control and renoprotection. Trimarchi H. Int J Nephrol Renovasc Dis 4 41-48 (2011)
  40. The catalytic mechanism of mouse renin studied with QM/MM calculations. Brás NF, Ramos MJ, Fernandes PA. Phys Chem Chem Phys 14 12605-12613 (2012)
  41. Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site. Politi A, Leonis G, Tzoupis H, Ntountaniotis D, Papadopoulos MG, Grdadolnik SG, Mavromoustakos T. Mol Inform 30 973-985 (2011)
  42. Design and discovery of new (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides as potent renin inhibitors. Mori Y, Ogawa Y, Mochizuki A, Nakamura Y, Sugita C, Miyazaki S, Tamaki K, Matsui Y, Takahashi M, Nagayama T, Nagai Y, Inoue S, Nishi T. Bioorg. Med. Chem. Lett. 22 7677-7682 (2012)
  43. Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation. Al-Nadaf AH, Taha MO. J. Mol. Graph. Model. 29 843-864 (2011)
  44. Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease. Serebruany VL, Malinin A, Barsness G, Vahabi J, Atar D. J Hum Hypertens 22 303-310 (2008)
  45. No increase in adverse events during aliskiren use among ontario patients receiving angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Gilbert CJ, Gomes T, Mamdani MM, Hellings C, Yao Z, Garg AX, Wald R, Harel Z, Juurlink DN. Can J Cardiol 29 586-591 (2013)
  46. Intratubular Renin-Angiotensin System in Hypertension. Suzaki Y, Prieto-Carrasquero MC, Kobori H. Curr Hypertens Rev 2 151-157 (2006)
  47. Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: discovery of DS-8108b, an orally active renin inhibitor. Nakamura Y, Fujimoto T, Ogawa Y, Namiki H, Suzuki S, Asano M, Sugita C, Mochizuki A, Miyazaki S, Tamaki K, Nagai Y, Inoue S, Nagayama T, Kato M, Chiba K, Takasuna K, Nishi T. Bioorg. Med. Chem. 21 3175-3196 (2013)
  48. New renin inhibitors with pseudodipeptidic units in P(1)-P(1') and P(2')-P(3') positions. Paruszewski R, Jaworski P, Winiecka I, Tautt J, Dudkiewicz J. Chem. Pharm. Bull. 50 850-853 (2002)
  49. Quantitative structure-activity relationship modeling of renin-inhibiting dipeptides. Udenigwe CC, Li H, Aluko RE. Amino Acids 42 1379-1386 (2012)
  50. Structure-based design and optimization of potent renin inhibitors on 5- or 7-azaindole-scaffolds. Matter H, Scheiper B, Steinhagen H, Böcskei Z, Fleury V, McCort G. Bioorg. Med. Chem. Lett. 21 5487-5492 (2011)
  51. Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors. Scheiper B, Matter H, Steinhagen H, Böcskei Z, Fleury V, McCort G. Bioorg. Med. Chem. Lett. 21 5480-5486 (2011)
  52. The P1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin. Yamaguchi Y, Menear K, Cohen NC, Mah R, Cumin F, Schnell C, Wood JM, Maibaum J. Bioorg. Med. Chem. Lett. 19 4863-4867 (2009)
  53. Development and validation of a HPLC-PDA bioanalytical method for the simultaneous estimation of Aliskiren and Amlodipine in human plasma. Mannemala SS, Nagarajan JS. Biomed. Chromatogr. 29 346-352 (2015)
  54. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor. Nakamura Y, Fujimoto T, Ogawa Y, Sugita C, Miyazaki S, Tamaki K, Takahashi M, Matsui Y, Nagayama T, Manabe K, Mizuno M, Masubuchi N, Chiba K, Nishi T. ACS Med Chem Lett 3 754-758 (2012)
  55. Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease. Antlanger M, Bernhofer S, Kovarik JJ, Kopecky C, Kaltenecker CC, Domenig O, Poglitsch M, Säemann MD. Ann. Med. 49 525-533 (2017)
  56. In silico analysis and molecular modeling of RNA polymerase, sigma S (RpoS) protein in Pseudomonas aeruginosa PAO1. Sedighi M, Moghoofei M, Kouhsari E, Pournajaf A, Emadi B, Tohidfar M, Gholami M. Rep Biochem Mol Biol 4 32-42 (2015)
  57. Mechanistic insights into the antifibrotic activity of aliskiren in the kidney. Zeisberg M, Müller GA. Hypertens. Res. 35 266-268 (2012)
  58. Renin inhibition activity by chitooligosaccharides. Park PJ, Ahn CB, Jeon YJ, Je JY. Bioorg. Med. Chem. Lett. 18 2471-2474 (2008)
  59. Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors. Mori Y, Ogawa Y, Mochizuki A, Nakamura Y, Fujimoto T, Sugita C, Miyazaki S, Tamaki K, Nagayama T, Nagai Y, Inoue S, Chiba K, Nishi T. Bioorg. Med. Chem. 21 5907-5922 (2013)
  60. Lepidium meyenii (Maca) Roots: UPLC-HRMS, Molecular Docking, and Molecular Dynamics. Ibrahim RM, Elmasry GF, Refaey RH, El-Shiekh RA. ACS Omega 7 17339-17357 (2022)
  61. Aliskiren and losartan trial in non-diabetic chronic kidney disease. Woo KT, Choong HL, Wong KS, Tan HK, Foo M, Fook-Chong S, Lee EJ, Anantharaman V, Lee GS, Chan CM. J Renin Angiotensin Aldosterone Syst 15 515-522 (2014)
  62. Combination renin-angiotensin system blockade with the renin inhibitor aliskiren in hypertension. Doulton TW, MacGregor GA. J Renin Angiotensin Aldosterone Syst 10 185-189 (2009)
  63. Grassystatins D-F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer. Al-Awadhi FH, Law BK, Paul VJ, Luesch H. J. Nat. Prod. 80 2969-2986 (2017)
  64. Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis. Sato A, Piao H, Nozawa Y, Morioka T, Kawachi H, Oite T. Clin. Exp. Nephrol. 16 539-548 (2012)
  65. Molecular dynamics studies on both bound and unbound renin protease. Brás NF, Fernandes PA, Ramos MJ. J. Biomol. Struct. Dyn. 32 351-363 (2014)
  66. Successful treatment of hypertension in anuric hemodialysis patients with a direct Renin inhibitor, aliskiren. Maeda Y, Araki Y, Uno T, Nishigaki K, Inaba N. J Rural Med 6 26-31 (2011)
  67. Aliskiren inhibits prorenin-induced human aortic smooth muscle cell migration. Ferri N, Panariti F, Ricci C, Maiocchi G, Corsini A. J Renin Angiotensin Aldosterone Syst 16 284-291 (2015)
  68. Clinical Implication of the Renin-angiotensin-aldosterone Blockers in Chronic Kidney Disease Undergoing Hemodialysis. Morishita Y, Kusano E, Nagata D. Open Cardiovasc Med J 8 6-11 (2014)
  69. Dietary peptides from the non-digestible fraction of Phaseolus vulgaris L. decrease angiotensin II-dependent proliferation in HCT116 human colorectal cancer cells through the blockade of the renin-angiotensin system. Luna-Vital DA, Liang K, González de Mejía E, Loarca-Piña G. Food Funct 7 2409-2419 (2016)
  70. Identification of novel human renin inhibitors through a combined approach of pharmacophore modelling, molecular DFT analysis and in silico screening. Gogoi D, Baruah VJ, Chaliha AK, Kakoti BB, Sarma D, Buragohain AK. Comput Biol Chem 69 28-40 (2017)
  71. New renin inhibitors containing pseudodipeptidic units in P3-P2 and P1-P1' positions. Paruszewski R, Jaworski P, Bodnar M, Dudkiewicz-Wilczyńska J, Roman I. Chem. Pharm. Bull. 53 1305-1309 (2005)
  72. Renin inhibition for hypertension: selecting the right role for a new class of drug. Bergset J, Storozynsky E, Bisognano JD. Am J Ther 17 182-187 (2010)
  73. Synthesis, biological evaluation and docking studies of octane-carboxamide based renin inhibitors with extended segments toward S3' site of renin. Wu Y, Shi C, Sun X, Wu X, Sun H. Bioorg. Med. Chem. 19 4238-4249 (2011)
  74. Targeting ACE and ECE with dual acting inhibitors. Hanessian S, Guesné S, Riber L, Marin J, Benoist A, Mennecier P, Rupin A, Verbeuren TJ, De Nanteuil G. Bioorg. Med. Chem. Lett. 18 1058-1062 (2008)
  75. A retrospective Aliskiren and Losartan study in non-diabetic chronic kidney disease. Woo KT, Choong HL, Wong KS, Tan HK, Foo M, Stephanie FC, Lee EJ, Anantharaman V, Lee GS, Chan CM. World J Nephrol 2 129-135 (2013)
  76. Aliskiren has chondroprotective efficacy in a rat model of osteoarthritis through suppression of the local renin-angiotensin system. Yan K, Shen Y. Mol Med Rep 16 3965-3973 (2017)
  77. Computational modeling and design of renin inhibitors. Subramanian G. Bioorg. Med. Chem. Lett. 23 460-465 (2013)
  78. Conformational analysis of aliskiren, a potent renin inhibitor, using high-resolution nuclear magnetic resonance and molecular dynamics simulations. Matsoukas MT, Zoumpoulakis P, Tselios T. J Chem Inf Model 51 2386-2397 (2011)
  79. Editorial Direct renin inhibitors in hypertension - approaching the moment of truth. Hedner T, Narkiewicz K, Oparil S, Kjeldsen SE. Blood Press. 21 267-268 (2012)
  80. Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors. Iijima D, Sugama H, Awai N, Takahashi Y, Togashi Y, Takebe T, Xie J, Shen J, Ke Y, Akatsuka H, Kawaguchi T, Takedomi K, Kashima A, Nishio M, Inui Y, Yoneda H, Xia G, Iijima T. ACS Med Chem Lett 13 1351-1357 (2022)
  81. Discovery of new sites for drug binding to the hypertension-related renin-angiotensinogen complex. Brás NF, Fernandes PA, Ramos MJ. Chem Biol Drug Des 83 427-439 (2014)
  82. Monitor: molecules and profiles. Barrett D, Langston S. Drug Discov. Today 6 52-53 (2001)
  83. Novel renin inhibitors containing derivatives of N-alkylleucyl-β-hydroxy-γ-amino acids. Winiecka I, Jaworski P, Mazurek AP, Marszałek D, Goldnik A, Sokulski D. J. Pept. Sci. 22 106-115 (2016)
  84. Optimizing interactions to protein binding sites by integrating docking-scoring strategies into generative AI methods. Sauer S, Matter H, Hessler G, Grebner C. Front Chem 10 1012507 (2022)
  85. Physicochemical characterisation, molecular docking, and drug-likeness evaluation of hypotensive peptides encrypted in flaxseed proteome. Ji D, Xu M, Udenigwe CC, Agyei D. Curr Res Food Sci 3 41-50 (2020)
  86. Protective Effects of Nanoparticle-Loaded Aliskiren on Cardiovascular System in Spontaneously Hypertensive Rats. Pechanova O, Barta A, Koneracka M, Zavisova V, Kubovcikova M, Klimentova J, Tӧrӧk J, Zemancikova A, Cebova M. Molecules 24 (2019)
  87. Retrospective ensemble docking of allosteric modulators in an adenosine G-protein-coupled receptor. Bhattarai A, Wang J, Miao Y. Biochim Biophys Acta Gen Subj 1864 129615 (2020)
  88. The development of a complementary pathway for the synthesis of aliskiren. Li LL, Ding JY, Gao LX, Han FS. Org. Biomol. Chem. 13 1133-1140 (2015)
  89. Three-step synthesis of cyclopropyl peptidomimetics. Dunlap N, Lankford KR, Pathiranage AL, Taylor J, Reddy N, Gouger D, Singer P, Griffin K, Reibenspies J. Org. Lett. 13 4879-4881 (2011)


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  1. The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor.. Rahuel J, Priestle JP, Grütter MG J Struct Biol 107 227-36 (1991)

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