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

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Cooper M, Receveur JM, Bjurling E, Norregaard PK, Nielsen PA, Skold N, Hogberg T

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

Bioorg Med Chem Lett. 2010 Jan 1;20(1):26-30. doi: 10.1016/j.bmcl.2009.11.047. Epub 2009 Nov 15.

PubMed ID

19954978 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rimonabant	Cannabinoid receptor 1	IC 50 (nM)	4.5	N/A	N/A	Details