RESUMO
We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.
Assuntos
Amino Álcoois/química , Receptores CCR2/antagonistas & inibidores , Amino Álcoois/farmacologia , Animais , Disponibilidade Biológica , CamundongosRESUMO
We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.
Assuntos
Benzimidazóis/farmacologia , Cicloexanos/química , Receptores CCR2/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We describe the design, synthesis, and evaluation, of gamma-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC(50)=1.0 nM and chemotaxis IC(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.
Assuntos
Cicloexanos/farmacologia , Glicina/análogos & derivados , Lactamas/química , Receptores CCR2/antagonistas & inibidores , Animais , Quimiotaxia/efeitos dos fármacos , Cicloexanos/química , Glicina/química , CamundongosRESUMO
A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).
Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Sítios de Ligação , Cálcio/química , Quimiocina CCL2/química , Quimiotaxia , Cicloexanos/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC(50)=1.3nM) and functional antagonism (calcium flux IC(50)=0.5nM and chemotaxis IC(50)=0.2nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.