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ACS medicinal chemistry letters
Sep 13, 2012;3 (9): 754-8.

Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.

Yuji Nakamura, Teppei Fujimoto, Yasuyuki Ogawa, Chie Sugita, Shojiro Miyazaki, Kazuhiko Tamaki, Mizuki Takahashi, Yumi Matsui, Takahiro Nagayama, Kenichi Manabe, Makoto Mizuno, Noriko Masubuchi, Katsuyoshi Chiba, Takahide Nishi
Author Information
  1. Yuji Nakamura: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  2. Teppei Fujimoto: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  3. Yasuyuki Ogawa: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  4. Chie Sugita: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  5. Shojiro Miyazaki: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  6. Kazuhiko Tamaki: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  7. Mizuki Takahashi: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  8. Yumi Matsui: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  9. Takahiro Nagayama: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  10. Kenichi Manabe: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  11. Makoto Mizuno: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  12. Noriko Masubuchi: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  13. Katsuyoshi Chiba: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  14. Takahide Nishi: Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 24900544 DOI: 10.1021/ml300168e

Abstract

A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.

Keywords

4-aminoadamantan-1-ol hypertension plasma renin activity renin inhibitor

References

  1. Chem Biol. 2000 Jul;7(7):493-504 [PMID: 10903938]
  2. Bioorg Med Chem Lett. 2012 Jul 15;22(14):4561-6 [PMID: 22726934]
  3. J Med Chem. 2002 May 23;45(11):2289-93 [PMID: 12014967]
  4. Am J Hypertens. 2004 Nov;17(11 Pt 2):16S-20S; quiz A2-4 [PMID: 15539106]
  5. Nat Rev Drug Discov. 2002 Aug;1(8):621-36 [PMID: 12402502]
  6. Kidney Int Suppl. 2005 Dec;(99):S57-65 [PMID: 16336578]
  7. Expert Rev Cardiovasc Ther. 2003 May;1(1):51-63 [PMID: 15030297]
  8. ACS Med Chem Lett. 2011 Aug 09;2(10):747-51 [PMID: 24900262]
  9. Bioorg Med Chem. 2007 Sep 1;15(17):5912-49 [PMID: 17574423]
  10. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5074-9 [PMID: 20673718]
  11. Lancet. 2007 Apr 7;369(9568):1208-19 [PMID: 17416265]
  12. J Med Chem. 2007 Oct 4;50(20):4832-44 [PMID: 17824680]
  13. Nat Rev Drug Discov. 2008 May;7(5):399-410 [PMID: 18340340]
  14. J Chem Soc Perkin 1. 1969;1:89-91 [PMID: 5813417]
  15. J Med Chem. 2009 Jun 25;52(12):3689-702 [PMID: 19358611]
  16. Bioorg Med Chem Lett. 2011 Jul 1;21(13):3970-5 [PMID: 21621998]
  17. Nephrol Dial Transplant. 2006 Jan;21(1):16-20 [PMID: 16280370]
  18. J Med Chem. 2010 Nov 11;53(21):7490-520 [PMID: 20731374]
  19. Am J Hypertens. 1992 Dec;5(12 Pt 2):247S-251S [PMID: 1290620]
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