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"Antagonism of CB agonist (CP 55,940)-induced hypotension in rat, expressed as ED50 (mg/kg, p.o.).

b Antagonism of CB agonist (WIN 55,212-2)-induced hypothermia in mouse, expressed as least effective dose (LED) (mg/kg, p.o.).

"Antagonism of CB agonist (CP 55,940)-induced hypotension in rat, expressed as ED50 (mg/kg, p.o.).

b Antagonism of CB agonist (WIN 55,212-2)-induced hypothermia in mouse, expressed as least effective dose (LED) (mg/kg, p.o.).

An X-ray diffraction study of (426) revealed the existence of a hydrogen bond between the N-atom at the 2-position of the dihydropyrazole ring and the hydrogen atom of the amidine. A series of Confort-generated conform-ers of (426) were generated and minimised (MOPAC, PM3) and then compared with the favoured trans-gauche Tg conformer [279] of rimonabant (382). The conformer of (426) which overlapped best with the Tg conformer of (382) was then docked into a reconstructed model of the CB1 receptor [281]. It was found that hydrogen bond was formed between one of the oxygen atoms of SO2 and the Asp-366:Lys-192 salt bridge. An additional H-bond was also observed between Ser-383 and the remaining SO2 oxygen atom. A stacking interaction could be envisaged between the 4-Cl-phenyl ring of (426) and the Phe-170 residue. Two hydrophobic pockets, defined by Trp-279, Phe-200, Trp-356 and Tyr-275, Trp-255, Phe-278 bind the two 4-Cl-phenyl rings.

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5 A2) compared with (426) (89.3 A2) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned.

IMIDAZOLE-, THIAZOLE-, PYRROLE- AND TRIAZOLE-BASED CBi RECEPTOR ANTAGONISTS

4,5-Diarylimidazole derivatives, exemplified by (448) have been claimed by Merck as either antagonists or inverse agonists of the CB1 receptor [298]. In this series of compounds, the central imidazole motif can be considered a bioisost-ere of the pyrazole core of rimonabant. A similar approach was utilised by Solvay Pharmaceuticals [299] in a patent application published shortly after that of Merck. The isomeric 1,2-diaryl-4-carboxamide nucleus (449) can again be considered as a structural isostere, serving to orient the two substituted aryl groups and carboxamide group in geometry analogous to that of (382). An alternative methylimidazole core, 1,2-diaryl-5-methylimidazole (450), was also utilised by Merck [300]. More recently, Pfizer has disclosed a series of novel imidazole derivatives useful in the treatment of obesity, alcoholism and depression [301]. The specified compound (451) was stated to have CB1 binding affinity in the range of 1-10 nM.

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