α,α-Cyclic aminoacids as useful scaffolds for the preparation of hNK2 receptor antagonists

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Abstract

MEN 15596 is a small molecule, potent and selective antagonist of NK2 receptor, possessing high affinity and potency at the guinea-pig and human receptors whose pharmacological characterization has been recently published. Here we report how the corresponding class of compounds was derived from a tri-peptide library and the first optimization round to improve both in vitro activity and physicochemical properties.

Graphical abstract

In the search for a novel class of hNK2 antagonists, compound 1 was identified from a tripeptide library. Subsequent optimization of binding affinity and physicochemical properties afforded 43, subnanomolar hNK2 antagonist.

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Acknowledgments

The authors thank G. Righetti and V. Caciagli for assistance in the synthesis of compounds, S. Mauro for analytical assistance, R.M. Catalioto for Caco-2 cells permeability test, D. Tagliacozzi for metabolic stability assessment, and S. Meini for biotesting. This work was supported in part by MIUR, Ministero dell’Istruzione, dell’Università e della Ricerca (Grant Ref. No. 63217).

References and notes (10)

  • C. Cialdai et al.

    Eur. J. Pharm.

    (2006)
  • S. Meini et al.

    Eur. J. Pharm.

    (2004)
  • D. Regoli et al.

    Pharmacology

    (1989)
  • C.A. Maggi et al.

    J. Autonom. Pharm.

    (1993)
  • Z.L. Gao et al.

    Curr. Med. Chem.

    (1999)
There are more references available in the full text version of this article.

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