ABSTRACT
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.
Subject(s)
Drug Design , Pyridines/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/metabolism , Adenosine A2 Receptor Antagonists/pharmacology , Binding Sites , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , HEK293 Cells , Humans , Molecular Docking Simulation , Palladium/chemistry , Protein Structure, Tertiary , Pyridines/metabolism , Pyridines/pharmacology , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/metabolism , Adenosine A2 Receptor Antagonists/pharmacokinetics , Benzoxazoles/metabolism , Benzoxazoles/pharmacokinetics , Caco-2 Cells , Cell Line, Tumor , Drug Design , Humans , Microsomes, Liver/metabolism , SolubilityABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Benzoxazoles/pharmacology , Drug Design , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Cell Death/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Models, Molecular , Molecular Structure , Solubility , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.
