RESUMO
Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Animais , Inibidores das Enzimas do Citocromo P-450 , Cães , Eosinófilos/citologia , Ligação de Hidrogênio , Camundongos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Ciclização , Ligação de Hidrogênio , Conformação Molecular , Ureia/química , Ureia/farmacologiaRESUMO
DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.
Assuntos
Compostos de Benzil/química , Compostos de Benzil/farmacologia , Inibidores do Citocromo P-450 CYP2D6 , Compostos de Fenilureia/química , Piperidinas/química , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Compostos de Benzil/síntese química , Bioensaio , Células Cultivadas , Humanos , Camundongos , Pan troglodytes , Compostos de Fenilureia/farmacologia , Piperidinas/síntese química , Receptores CCR3 , Relação Estrutura-AtividadeRESUMO
Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Piperidinas/química , Receptores CCR3 , Relação Estrutura-AtividadeRESUMO
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
Assuntos
Cicloexanos/síntese química , Compostos de Fenilureia/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células CHO , Células CACO-2 , Cálcio/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Cricetinae , Cicloexanos/química , Cicloexanos/farmacologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/fisiologia , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Permeabilidade , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores CCR3 , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.
Assuntos
Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Ureia/síntese química , Sinalização do Cálcio/efeitos dos fármacos , Quimiocina CCL11 , Quimiocinas CC/farmacologia , Interações Medicamentosas , Eosinófilos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Piperidinas/farmacologia , Ligação Proteica , Receptores CCR3 , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
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.