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vivo tests, including hypomobility, antinociception and hypothermia. Variations of the pyrazole substitution pattern in positions 1, 4 and 5 led to compounds with varying affinity that consistently behaved as antagonists in vivo. Introduction of ether moieties into the 3-position of the pyrazole core led to the identification of both partial agonists and antagonists. For example, compound 0-1043 (387) retained a K of 53 nM and demonstrated antagonism in vivo. An analogue, in which the amide was replaced with a ketone (0-1271) (388), retained a K of 82 nM and again demonstrated antagonism in vivo.

Makriyannis and Liu claimed a series of pyrazole analogues in a patent application published in 2003 [272]. Of the 29 compounds specifically exemplified in the patent application, compound (389) was demonstrated to reduce lever presses when administered to rats that were trained to expect delivery of a food pellet as the outcome. It was proposed that the reduction in lever pressing was the result of decreased appetite brought about by CB1 receptor antagonism.

Horti and co-workers [273] published on their studies to produce analogues of rimonabant with reduced lipophilicity. The aim of the work was to produce ligands for positron emission tomography (PET) studies in humans. Highly lipophilic ligands were noted to be a problem due to resulting high levels of non-specific binding. An additional limiting factor in the work was the need to be able to introduce an appropriate atom for a PET labelling study (18F, 76Br or 11C). NIDA-41020 (390) retained high CB1 receptor affinity (K; = 4.1 nM, (382) K; = 1.8 nM in the same assay format) and a reduced lipophilicity in comparison with (382) (elog Doct values of 4.78 and 5.36, respectively).

Several studies have been reported on the application of conformational restraint to the 1,5-diaryl-pyrazole series in an attempt to provide compounds with modified properties. In one approach, a Sanofi-Synthelabo patent application claimed a series of conformationally restrained compounds, exemplified by compound (391). Compounds of the invention were stated to be CB1 receptor antagonists with K values below 5 x 10"7M and selectivity over CB2 receptors of at least 10-fold [274].

Lange and co-workers [275] published on conformationally restrained analogues of rimonabant (382), again constraining the pyrazole 4-position and the 5-aryl substituent into a ring system. The highest affinity compound within the series was compound (392), which displayed a pK value of 7.2 ((382) pK 7.6 in the same assay). This compound (392) was found to be slightly more potent than (382) in a cell-based functional assay for CB1 antagonism (pA2 values of 8.8 and 8.6, respectively). In a subsequent publication, Ruiu et al. [276] synthesised and characterised NESS-0327 (393). This compound had also been prepared and tested in the publication from Lange et al. (393) was reported to show higher affinity for the CB1 receptor than (382) (K values of 350 fM and 1.8 nM, respectively), in addition to higher affinity for the CB2 receptor (K values of 21 and 514 nM, respectively). Selectivity for the CB1 receptor over the CB2 receptor was calculated at more than 60,000-fold for (393). Potent antagonism was demonstrated in a variety of in vitro and in vivo paradigms for (393).

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