RESUMO
A novel cyclohexenyl series of CCR2 antagonists has been discovered. This series of small, rigid compounds exhibits submicromolar binding affinity for CCR2. Modification of the substituents on the cyclohexene ring led to the identification of potent CCR2 antagonists. Progress from initial lead 5 (IC50=700nM) to (-)-38 (IC50=9.0nM) is discussed.
Assuntos
Cicloexenos/química , Cicloexenos/farmacologia , Receptores CCR2/antagonistas & inibidores , Cicloexenos/síntese química , Descoberta de Drogas , Humanos , Modelos Moleculares , Receptores CCR2/metabolismo , Relação Estrutura-AtividadeRESUMO
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
RESUMO
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Descoberta de Drogas , Fenilalanina/farmacologia , Prolina/farmacologia , Triptofano/farmacologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbazóis/administração & dosagem , Carbazóis/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fenilalanina/administração & dosagem , Fenilalanina/química , Prolina/administração & dosagem , Prolina/química , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Triptofano/administração & dosagem , Triptofano/químicaRESUMO
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
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.