RESUMO
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.
Assuntos
Acetanilidas/síntese química , Antineoplásicos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Triazinas/síntese química , Acetanilidas/farmacocinética , Acetanilidas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aurora Quinase A , Aurora Quinases , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Histonas/metabolismo , Humanos , Modelos Moleculares , Transplante de Neoplasias , Fosforilação , Ligação Proteica , Ratos , Ratos Nus , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologiaRESUMO
A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.
Assuntos
Química Farmacêutica/métodos , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/química , Animais , Inibidores do Citocromo P-450 CYP2D6 , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Modelos Químicos , Conformação Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Assuntos
Fármacos Antiobesidade/síntese química , Hidantoínas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Compostos de Espiro/síntese química , Fármacos Antiobesidade/farmacologia , Desenho de Fármacos , Humanos , Hidantoínas/farmacologia , Cinética , Ligação Proteica , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Assuntos
Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Concentração Inibidora 50 , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Estrutura Molecular , Pirrolidinas/química , Ratos , Receptores do Hormônio Hipofisário/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).
Assuntos
Receptores do Hormônio Hipofisário/antagonistas & inibidores , Ureia/química , Ureia/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.