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Investigation of a 2-amido series was also carried out by Meurer et al. (Table 6.48). These compounds were found to be generally less potent than the 2-alkoxy-3-amido series with (545), the closest analogue of (382), among the most potent. In addition, the n-hexyl (540) and 4-heptyl (541) analogues were found to have comparable affinity, as was the benzyl congener (547). The relatively poor binding of the 2- and 3-amido pyridine series compared with (382) was ascribed to either the difference in ring size between pyridine and pyrazole resulting in a slight change in relative orientation of substitu-ents, and/or the basicity of the nitrogen and finally the absence of a neighbouring methyl group to force the amide group of rimonabant into a position perpendicular to the pyrazole ring.

In vivo studies were also performed on those compounds deemed to have the most favourable binding and functional assay data, (521) and (531). Pharmacokinetic studies carried out on Sprague-Dawley rats (1 mg/kg i.v., 2mg/kg p.o.) using compound (521) suggested favourable i.v. PK properties (AUCnom = 9.3mMhkg/mg; Clp = 3.6ml/min/kg; Vdss = 0.8L/kg; tV2 = 3.6 h), moderate oral absorption (F — 27%) but slow brain penetration and a low brain:plasma ratio (B : P — 0.03—0.26 at 0.25-4 h). Compound (521) was subsequently investigated in a food intake and body weight loss study using diet-induced obese rats. In contrast to (382), oral administration of (521) and 1, 3 and 10mg/kg did not lead to an immediate reduction in food intake at any of the doses, however after 18h after dosing at 10mg/kg, a cumulative but non-significant (p >0.05) 22% reduction in food intake and a dose-dependent weight loss (1 g compared with an 8 g gain for the vehicle-treated animals) was observed. It was postulated that the slow CNS penetration witnessed in the earlier PK study was preventing an immediate effect on the food intake.

Pyrazines have been utilised first by AstraZeneca [320-325] and subsequently by Bristol-Myers Squibb [326]. Although no specific biological data were presented in the initial two AstraZeneca patent applications, compounds including the specified (548) are claimed to have IC50 values less than 1 mM with the most preferred compounds having an IC50 value of less than 200 nM. Nine compounds are specifically claimed in the later AstraZeneca application [322] including (549) in which the N-piperidin-1-yl carboxamide of (382) is replaced with the bioisosteric piperidin-1-yl-oxy-carbonyl. Subsequently, a tetrazole-containing 5,6-bis(4-methylphenyl)-pyrazine derivative (550) was reported to have an IC50 of 1.4 nM [323]. A related tetrasubstituted compound, (551), which had been disclosed ge-nerically in an earlier AstraZeneca application [321], has been specifically claimed [324]. The affinity of this compound for the CB1 receptor was described only as less than 1 mM. Finally, from AstraZeneca, a third series of tetrasubstituted pyrazines was revealed [327], of which compound (552) was stated to have excellent CB1 affinity (1.8 nM). The now-familiar diaryl-pyrazine carboxamides have more recently been the subject of a patent application from Bristol-Myers Squibb [326]. Of the several compounds claimed, (553) shows that a hydroxymethyl functionality is tolerated adjacent to the carboxamide nitrogen but no specific data were presented in the application.

(549) R1 = Cl, X = O
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