Scaffold hopping strategy toward original pyrazolines as selective CB2 receptor ligands

In line of a scaffold hopping strategy of pyrazole structures, especially known as potent CB2 receptor antagonists, we exploited an original and convergent synthesis of a new class of C4-benzyl pyrazolines and derivatives from readily available hydrazones and enones (two or three steps). Making use of a mixture of resin supported reagents strategy an efficient domino process allowed the easy construction of various dihydropyrazoles in 63–83% yields. The obtained family of pyrazolines featured significant hCB2/hCB1 selectivity in favor of hCB2 receptors while more than 1000–3000 nM affinity was only measured for hCB1 receptors. This is closely related to pyrazole SR144528 inverse agonist/antagonist, although a partial agonist behavior in the [35S]-GTPγS binding assay was mainly measured in our case pointing out a functional switch in action. Furthermore, this hCB2 selectivity is unique within the pyrazoline CB ligands although the affinity ranging from 251 to 689 nM remains to be improved which give, however, an opportunity for further structure–activity relationship.

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► Synthesis of new C4-benzyl pyrazolines making use of a resin based reagent strategy.
► Convergent approach from hydrazones and Weinreb amides for structure modulation.
► Scaffold hopping strategy of pyrazole structures known as CB2 receptor antagonists.
► The obtained pyrazolines featured a unique CB2/CB1 selectivity in favor of CB2.
► Agonist behavior highlighting a functional switch versus pyrazole homologs.