Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists

doi:10.1016/j.bmcl.2009.11.047

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 1, 1 January 2010, Pages 26-30

https://doi.org/10.1016/j.bmcl.2009.11.047 Get rights and content

Abstract

A chemically diverse library of secondary and tertiary 4-cyanomethyl-1,5-diphenyl-1H-pyrazole-3-carboxamides was synthesized to enable mapping of the SAR, in the eastern amide region, with regard to CB1 antagonist activity, This study was initiated as a prelude to the design and synthesis of possible CB1 antagonists that do not readily pass the blood–brain-barrier. In general a range of modifications were found to be tolerated in this part of the molecule, although polar and especially charged groups did to a degree reduce the CB1 antagonistic activity. Several compounds with single-digit or even sub-nanomolar potency, suitable for further elaboration of the nitrile moiety, were identified.

Graphical abstract

The SAR was explored in the eastern R-group as a prelude for transforming the nitrile group into compounds that are not readily passing the blood–brain-barrier.

Section snippets

Acknowledgements

The authors thank Rokhsana Andersen and Helle Iversen for excellent technical assistance.

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Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists

Abstract

Graphical abstract

Section snippets

Acknowledgements

Pharmacol. Res.

Best Pract. Res. Clin. Endocrinol. Metab.

Int. J. Obesity

Endocrinology

Expert Opin. Emerging Drugs

Drug Discovery Today

Obes. Rev.

Best Pract. Res. Clin. Endocrinol. Metab.

Diabetologia

Neuroendocrinology

Int. J. Obes.

Curr. Top. Med. Chem.

Curr. Top. Med. Chem.

Curr. Med. Chem.