CCRl Small Molecule Antagonists RP23618 1is an early example of a nonpep

Agonist Molecule

tide small molecule chemokine antagonist

(84). This compound inhibits 125I-RANTES binding to THP-1 cell membranes (IC50 = 3 fjM). The chemokine receptors CCRl and CCR2 have been detected by RT-PCR as being present on this cell type (62). However, because (1) inhibits RANTES-induced chemotaxis and has no effect on an MCP-l-stimu-lated chemotactic response, this compound appears to be CCRl selective. Because (1)is not competitive with RANTES, it is presumed to bind at an allosteric site.

There is a limited structure-activity relationship (SAR) provided around this series. However, an optimal chain length of three carbon atoms between the phenothiazine and the piperidine is demonstrated. The two-carbon-linked homolog has significantly reduced activity (IC50 < 20% at 30 tiM) and the four-carbon tether is at least 3 times less active than (1).

A similar pharmacophore finding was noted for early leads from the Berlex group

(85). HEK293 cells containing the CCRl receptor were evaluated for binding with another CCRl ligand, MlP-la. The three-carbon-tethered dibenzothiepine (2) was a potent

I LOH

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