Discovery of a novel CCR3 selective antagonist

Small molecule antagonists for chemokine CCR3 receptors

“…Another study revealed a similar compound with dual antagonizing effects against CCR1 and CCR3, and based on its chemical structure several functional groups were proposed to be important for antagonism. 37 Besides the presence of hydrophobic groups and a charged nitrogen atom for electrostatic interactions with the receptor, a carbonyl group appears to be important as a hydrogen-bond acceptor. Furthermore, it was reasoned that one might replace the cationic quaternary nitrogen atom, which might hinder oral absorption, by a tertiary amine group.…”

“…[37][38][39] The hydrophobic groups in these compounds are a N-benzyl group attached to the piperidine ring and a 2-benzothiazolethio moiety next to the amide. Compound 2 showed weak affinity for CCR3 (IC 50 value of 1 mM) and was only 4-fold selective over CCR1.…”

“…32 For chemokine receptors, several dual antagonists have been reported in literature, for example, dual CCR1/ CCR3, CCR2/CCR5, or CXCR1/CXCR2 antagonists. 4,36,37 In addition, dual antagonists were described recently that target the unrelated receptors CCR3 and the histamine receptor H1 (for example 4c). 32,42,65,66 The reason for the inhibition of such different types of receptors was suggested to lie in the fact that small nonpeptide antagonists such as 4c generally bind to allosteric sites in the receptor and do therefore not require similar binding pockets.…”

Structure-Activity Relationships of 2-(Benzothiazolylthio)acetamide Class of CCR3 Selective Antagonist

“…The lead compound was divided into three sub-structures (A-, B-, and C-parts), and optimization of each sub-structure was performed based on the previous results. 13) (Fig. 2) First, effects of substituent(s) (A-part) on the benzene ring on the binding affinities to CCR3 and CCR1 receptors were examined ( Table 1).…”

Selective suppression of leukocyte recruitment in allergic inflammation

“…An alternative is to inhibit eosinophil recruitment into tissue, where the Eotaxins are thought to play a major part, acting via CCR3. Several low molecular weight CCR3 receptor antagonists have been developed that can effectively block eosinophil migration (White et al 2000, Sabroe et al 2000, Naya et al 2001, Varnes et al 2004). Some of these compounds have reached the early stages of clinical trials.…”