RESUMO
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
Assuntos
Antiasmáticos/química , Antiasmáticos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Alquilação , Amidas/química , Amidas/metabolismo , Cálcio/metabolismo , Quimiocina CCL11 , Quimiocinas CC/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Piperidinas/química , Receptores CCR3 , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.