RESUMO
Imidazo[1,2a]pyridines have gained much interest in the field of medicinal chemistry research. In the aim of accessing new privileged structure, we decided to design and synthesize 8-aminated-imidazo[1,2a]pyridines substituted on positions 2 and 6. This scaffold, rarely found in the literature, was obtained via palladium-catalyzed coupling reactions (Suzuki reaction or N-hydroxysuccinimidyl activated ester method) and tested on adenosine receptor A2A. We demonstrated how incorporation of an exocyclic amine enhanced affinity towards this receptor while maintaining low cytotoxicity.
Assuntos
Desenho de Fármacos , Piridinas/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Sítios de Ligação , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Paládio/química , Estrutura Terciária de Proteína , Piridinas/metabolismo , Piridinas/farmacologia , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 µm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 µm) without being cytotoxic at 100 µm. This compound, along with low-molecular weight compound D1 (Ki = 10 µm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Benzoxazóis/farmacologia , Desenho de Fármacos , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Benzoxazóis/síntese química , Benzoxazóis/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
We have recently reported a series of 2-furoyl-benzoxazoles as potential A2A adenosine receptor (A2AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hA2AR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hA2AR, we explored the C5- and C7-position of hits 1 and 2 based on docking studies. These modifications led to compounds with nanomolar-range affinity (e.g. 6a, Ki = 40 nM) and high antagonist activity (e.g. 6a, IC50 = 70.6 nM). Selected compounds also exhibited interesting in vitro DMPK (Drug Metabolism and Pharmacokinetics) properties including high solubility and low cytotoxicity. Therefore, the benzoxazole ring appears as a highly effective scaffold for the design of new A2A antagonists.
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Benzoxazóis/metabolismo , Benzoxazóis/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , SolubilidadeRESUMO
In the aim of identifying new privileged structures, we describe the 5-steps synthesis of cyclic guanidine compounds "tetrahydroisoquinoline-iminoimidazolines" derived from tetrahydroisoquinoline-hydantoin core. In order to evaluate this new minimal structure and the impact of replacing a carbonyle by a guanidine moiety, their affinity towards adenosine receptor A2A was evaluated and compared to those of tetrahydroisoquinoline-hydantoin compounds.