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A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore.

Ostermann N, Ruedisser S, Ehrhardt C, Breitenstein W, Marzinzik A, Jacoby E, Vangrevelinghe E, Ottl J, Klumpp M, Hartwieg JC, Cumin F, Hassiepen U, Trappe J, Sedrani R, Geisse S, Gerhartz B, Richert P, Francotte E, Wagner T, Krömer M, Kosaka T, Webb RL, Rigel DF, Maibaum J, Baeschlin DK
J Med Chem 56 2196-206 (2013)
Related entries: 4gj8, 4gj9, 4gja, 4gjb, 4gjd

Cited: 10 times
EuropePMC logo PMID: 23360239

Abstract

A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.

Reviews citing this publication (2)

  1. Twenty years on: the impact of fragments on drug discovery. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Nat Rev Drug Discov 15 605-619 (2016)
  2. Recent progress on the discovery of non-peptidic direct renin inhibitors for the clinical management of hypertension. Yokokawa F. Expert Opin Drug Discov 8 673-690 (2013)

Articles citing this publication (8)

  1. Mastering tricyclic ring systems for desirable functional cannabinoid activity. Petrov RR, Knight L, Chen SR, Wager-Miller J, McDaniel SW, Diaz F, Barth F, Pan HL, Mackie K, Cavasotto CN, Diaz P. Eur J Med Chem 69 881-907 (2013)
  2. Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor. Imaeda Y, Tokuhara H, Fukase Y, Kanagawa R, Kajimoto Y, Kusumoto K, Kondo M, Snell G, Behnke CA, Kuroita T. ACS Med Chem Lett 7 933-938 (2016)
  3. 4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides. Meyers MJ, Liu J, Xu J, Leng F, Guan J, Liu Z, McNitt SA, Qin L, Dai L, Ma H, Adah D, Zhao S, Li X, Polino AJ, Nasamu AS, Goldberg DE, Liu X, Lu Y, Tu Z, Chen X, Tortorella MD. J Med Chem 62 3503-3512 (2019)
  4. 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)
  5. 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)
  6. Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors. Imaeda Y, Tawada M, Suzuki S, Tomimoto M, Kondo M, Tarui N, Sanada T, Kanagawa R, Snell G, Behnke CA, Kubo K, Kuroita T. Bioorg Med Chem 24 5771-5780 (2016)
  7. Novel approach of fragment-based lead discovery applied to renin inhibitors. Tawada M, Suzuki S, Imaeda Y, Oki H, Snell G, Behnke CA, Kondo M, Tarui N, Tanaka T, Kuroita T, Tomimoto M. Bioorg Med Chem 24 6066-6074 (2016)
  8. trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: prime site exploration using an amino linker. Lorthiois E, Cumin F, Ehrhardt C, Kosaka T, Sellner H, Ostermann N, Francotte E, Wagner T, Maibaum J. Bioorg Med Chem Lett 25 1782-1786 (2015)


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