192703-20-1

Upstream product

• 1449691-95-5 ethyl 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxylate 
• 1029295-67-7 ethyl 5-(4-chloro-3-methylphenyl)-1H-pyrazole-3-carboxylate 
• 37074-39-8 4-chloro-3-methylacetophenone 
• 475471-20-6 4-(4-chloro-3-methylphenyl)-2,4-dioxobutyric acid ethyl ester 
• 192702-07-1 5-(4-chloro-3-methyl-phenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxylic acid 

Downstream Products

• 192703-06-3 SR 144528 
• 1449691-93-3 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]-1H-pyrazole-3-carboxamide 

Relevant academic research and scientific papers

Tritiation of the cannabinoid receptor antagonist SR144528 involving lithium aluminum tritide reduction; assessment of the kinetic isotope effect by 3H-NMR

The cannabinoid receptor antagonist SR144528 was synthesized by an approach that enabled the incorporation of high specific activity tritium label while circumventing the lability of the target compound to catalytic hydrogenation. Lithium aluminum tritide

The importance of hydrogen bonding and aromatic stacking to the affinity and efficacy of cannabinoid receptor CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3, 3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528)

Despite the therapeutic promise of the subnanomolar affinity cannabinoid CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl) methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl] -1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB 2 inactive state model that were then tested via compound synthesis, binding, and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenchyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogues.

3-pyrazolecarboxamide derivatives having cannabinoid receptor affinity

The present invention relates to compounds of the formula STR1 in which: X 1 is a group --NR 1 R 2 or a group --OR 2 ;g 2, g 3, g 4, g 5, g 6 and w 2, w 3, w 4, w 5, w 6 are identical or different and are each independently hydrogen, a halogen atom, a (C 1 -C 4)alkyl, a (C 1 -C 4)alkoxy, a trifluoromethyl, a nitro or a (C 1 -C 4)alkylthio, with the proviso that at least one of the substituents g 2, g 3, g 4, g 5, g 6 and at least one of the substituents w 2, w 3, w 4, w 5, w 6 are other than hydrogen;R 1 is hydrogen or a (C 1 -C 4)alkyl;R 2 is a non-aromatic (C 3 -C 15)carbocyclic radical which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C 1 -C 4)alkyl and a (C 1 -C 4)alkoxy;R 3 is hydrogen or a group --CH 2 R 6 ; andR 4 and R 5 are each independently a hydrogen, a (C 1 -C 4)alkyl or a trifluoromethyl;or else R 4 is hydrogen and R 5 and w 6 together constitute an ethylene or trimethylene radical; andR 6 is hydrogen, a (C 1 -C 4)alkyl, a fluorine, a hydroxyl, a (C 1 -C 5)alkoxy, a (C 1 -C 5)alkylthio, a hydroxy(C 1 -C 5)alkoxy, a cyano, a (C 1 -C 5)alkylsulfinyl or a (C 1 -C 5)alkylsulfonyl with the proviso that when the substituents g 2, g 3, g 4, g 5 and/or g 6 are a (C 1 -C 4)alkyl R 6 is only hydrogen;to a process for their preparation and to the pharmaceutical compositions in which they are present.These compounds have a good affinity for the peripheral cannabinoid receptors.