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Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.

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
J Med Chem 52 3689-702 (2009)
Related entries: 3g6z, 3g70

Cited: 30 times
EuropePMC logo PMID: 19358611

Abstract

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

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Reviews citing this publication (5)

  1. New and unusual scaffolds in medicinal chemistry. Marson CM. Chem Soc Rev 40 5514-5533 (2011)
  2. A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors. Siragy HM. Vasc Health Risk Manag 7 297-313 (2011)
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  4. The role of direct renin inhibition in clinical practice: focus on combination therapy. Rashid HU, Mende C. Am J Cardiovasc Drugs 11 303-315 (2011)
  5. Renin-angiotensin-aldosterone system blockade in high-risk hypertensive patients: current approaches and future trends. Gullapalli N, Bloch MJ, Basile J. Ther Adv Cardiovasc Dis 4 359-373 (2010)

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  1. Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors. John S, Thangapandian S, Arooj M, Hong JC, Kim KD, Lee KW. BMC Bioinformatics 12 Suppl 14 S4 (2011)
  2. Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility. Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA. ACS Med Chem Lett 2 747-751 (2011)
  3. New classes of potent and bioavailable human renin inhibitors. Remen L, Bezençon O, Richard-Bildstein S, Bur D, Prade L, Corminboeuf O, Boss C, Grisostomi C, Sifferlen T, Strickner P, Hess P, Delahaye S, Treiber A, Weller T, Binkert C, Steiner B, Fischli W. Bioorg. Med. Chem. Lett. 19 6762-6765 (2009)
  4. 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)
  5. 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)
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  9. 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)
  10. Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors. Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F. ACS Med Chem Lett 5 787-792 (2014)
  11. 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)
  12. Pharmacokinetics, pharmacodynamics, and tolerability of ACT-077825, a new direct renin inhibitor after multiple-ascending doses in healthy subjects. Nicolas LB, Gutierrez M, Binkert C, Dingemanse J. J. Cardiovasc. Pharmacol. 61 42-50 (2013)
  13. 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)
  14. An integrated computational workflow for efficient and quantitative modeling of renin inhibitors. Subramanian G, Rao SN. Bioorg. Med. Chem. 20 851-858 (2012)
  15. Molecular dynamics studies on both bound and unbound renin protease. Brás NF, Fernandes PA, Ramos MJ. J. Biomol. Struct. Dyn. 32 351-363 (2014)
  16. Comprehending renin inhibitor's binding affinity using structure-based approaches. Subramanian G, Rao SN. Bioorg. Med. Chem. Lett. 23 6667-6672 (2013)
  17. Effect of Multiple-Dose Diltiazem on the Pharmacokinetics of the Renin Inhibitor ACT-077825. Dingemanse J, Nicolas LB, van Bortel L. Clin Pharmacol Drug Dev 2 113-119 (2013)
  18. 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)
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  20. 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 K, Suresh R, Kumar HY, Kumar BRP, Murthy NBS. Bioorg. Med. Chem. 28 115466 (2020)
  21. 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)
  22. 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)
  23. Selective Csp3-F Bond Functionalization with Lithium Iodide. Balaraman K, Kyriazakos S, Palmer R, Thanzeel FY, Wolf C. Synthesis (Stuttg) 54 4320-4328 (2022)
  24. Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines. Abell JC, Bold CP, Vicens L, Jentsch T, Velasco N, Tyler JL, Straker RN, Noble A, Aggarwal VK. Org Lett 25 400-404 (2023)


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