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Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety.

Mack H, Baucke D, Hornberger W, Lange UE, Seitz W, Höffken HW
Bioorg Med Chem Lett 16 2641-7 (2006)
Cited: 9 times
EuropePMC logo PMID: 16517159

Abstract

The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.

Reviews citing this publication (1)

  1. Looking at the proteases from a simple perspective. Castro HC, Abreu PA, Abreu PA, Geraldo RB, Martins RC, dos Santos R, Loureiro NI, Cabral LM, Rodrigues CR. J. Mol. Recognit. 24 165-181 (2011)

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  3. Asymmetric organocatalytic allylic substitution of Morita-Baylis-Hillman carbonates with allylamines for the synthesis of 2,5-dihydropyrroles. Sun W, Ma X, Hong L, Wang R. J. Org. Chem. 76 7826-7833 (2011)
  4. Enantioselective organocatalytic one-pot amination/aza-Michael/aldol condensation reaction sequence: synthesis of 3-pyrrolines with a quaternary stereocenter. Desmarchelier A, Coeffard V, Moreau X, Greck C. Chemistry 18 13222-13225 (2012)
  5. Preparation of L-proline based aeruginosin 298-A analogs: optimization of the P1-moiety. Wang G, Goyal N, Hopkinson B. Bioorg. Med. Chem. Lett. 19 3798-3803 (2009)
  6. Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria. Yang S, Shi W, Xing D, Zhao Z, Lv F, Yang L, Yang Y, Hu W. Eur J Med Chem 86 133-152 (2014)
  7. Purification and characterization of thrombin from camel plasma: interaction with camel tick salivary gland thrombin inhibitor. Ibrahim MA, Masoud HMM. J Genet Eng Biotechnol 21 7 (2023)
  8. Synthesis of functionalized 2,5-dihydropyrrole derivatives via a convenient [3 + 2] annulation of azomethine ylides with allenoates. Huang Z, Dai Z, Zhu J, Yang F, Zhou Q. Org. Biomol. Chem. 16 6638-6646 (2018)


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