title: Discovery of a novel CCR3 selective antagonist.
abstract: In searching for a novel CCR3 receptor antagonist, we designed a library that included a variety of carboxamide derivatives based on the structure of our potent antagonists for human CCR1 and CCR3 receptors, and screened the new compounds for inhibitory activity against 125I-Eotaxin binding to human CCR3 receptors expressed in CHO cells. Among them, two 2-(benzothiazolethio)acetamide derivatives (1a and 2a) showed binding affinities with IC50 values of 750 and 1000 nM, respectively, for human CCR3 receptors. These compounds (1a and 2a) also possessed weak binding affinities for human CCR1 receptors. We selected la as a lead compound for derivatization to improve in vitro potency and selectivity for CCR3 over CCRI receptors. Derivatization of la by incorporating substituents into each benzene ring of the benzothiazole and piperidine side chain resulted in the discovery of a compound (1b) exhibiting 820-fold selectivity for CCR3 receptors (IC50 = 2.3 nM) over CCR1 receptors (IC50 = 1900 nM). This compound (1b) also showed potent functional antagonist activity for inhibiting Eotaxin (IC50 = 27 nM)- or RANTES (IC50 = 13 nM)-induced Ca2+ increases in eosinophils.
authors.affiliation: Banyu Tsukuba Research Institute, Ibaraki, Japan. nayaak@banyu.co.jp
authors.forename: A
authors.initials: A
authors.lastname: Naya
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.forename: K
authors.initials: K
authors.lastname: Ohwaki
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: K
authors.initials: K
authors.lastname: Noguchi
authors.forename: N
authors.initials: N
authors.lastname: Ohtake
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D052160:Benzothiazoles; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D019742:Chemokines, CC; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D052160:Benzothiazoles; C515456:CCL11 protein, human; C515300:CCR1 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D013844:Thiazoles; C005465:benzothiazole