Investigation of the substitution patterns at the 2-position of the piperidine group led to the identification of compound 7 which contains a 2-pentanol substituent (CCR3 binding (IC5o= 1 nM) (46). The erythro diastereomer, the hydroxy group, and the chain length are each critical for optimal potency.
In compounds 8 and 9, conformational rigidity is obtained via a trans a, p-unsaturated (cinnamoyl) ketone. In this design, the usual methylene link between the phenyl group to the 4-position of the piperidine can be replaced by an ether linker as in compound 8 (CCR3 binding IC50 = 2.8 nM) or a carbonyl linker as in compound 9 (CCR3 binding IC50 = 2 nM) (47-49). Compound 10 offers a novel twist to this design (CCR3 binding IC50 = 1 nM) (50). The use of an azetldine ring in place of a piperidine ring suggests that the latter is not required. To compensate for the smaller ring, the backbone is extended and the cinnamoyl group is switched from a ketone to an amide connection.
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