420137-90-2

Upstream product

• 620-08-6 4-methoxypyridine 
• 420137-88-8 1-benzyl-5,5-dibromo-6-imino-dihydro-pyrimidine-2,4-dione 
• 72816-87-6 6-amino-1-benzyl-5-bromo-2,4(1H)-pyrimidinedione 
• 41862-11-7 1-benzyl-6-aminouracil 
• 538-32-9 benzylurea 

Relevant academic research and scientific papers

Development of Covalent Ligands for G Protein-Coupled Receptors: A Case for the Human Adenosine A3 Receptor

The development of covalent ligands for G protein-coupled receptors (GPCRs) is not a trivial process. Here, we report a streamlined workflow thereto from synthesis to validation, exemplified by the discovery of a covalent antagonist for the human adenosine A3 receptor (hA3AR). Based on the 1H,3H-pyrido[2,1-f]purine-2,4-dione scaffold, a series of ligands bearing a fluorosulfonyl warhead and a varying linker was synthesized. This series was subjected to an affinity screen, revealing compound 17b as the most potent antagonist. In addition, a nonreactive methylsulfonyl derivative 19 was developed as a reversible control compound. A series of assays, comprising time-dependent affinity determination, washout experiments, and [35S]GTPγS binding assays, then validated 17b as the covalent antagonist. A combined in silico hA3AR-homology model and site-directed mutagenesis study was performed to demonstrate that amino acid residue Y2657.36 was the unique anchor point of the covalent interaction. This workflow might be applied to other GPCRs to guide the discovery of covalent ligands.

Structure-Affinity Relationships and Structure-Kinetics Relationships of Pyrido[2,1-f]purine-2,4-dione Derivatives as Human Adenosine A3 Receptor Antagonists

We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A3 receptor (hA3R) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of k

Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A3 adenosine receptor antagonists

1H,3H-Pyrido[2,1-f]purine-2,4-diones, which can be described as fused xanthine structures, have been synthesized by a novel synthetic procedure, and their affinities for the human adenosine A1, A2A, and A3 receptors have been evaluated in radioligand binding studies. The synthetic procedure employed was developed in our laboratory and involved a two-step one-pot reaction that consists of the treatment of 6-aminouracil derivatives with N-bromosuccinimide to generate a 5,5-dibromo-6-imino intermediate that reacts "in situ" with pyridine, 4-methoxypyridine, 4-tert-butylpyridine, or 4-phenylpyridine to afford the corresponding 1H,3H-pyrido-[2,1-f]purine-2,4-diones (2-5). Functionalization at the N3 position in compounds 2-5 was performed by reaction with DBU and different alkyl, alkenyl, alkynyl, or benzyl halides. Binding studies at human adenosine A1, A2A, and A3 receptors revealed significant antagonist effects in the low nanomolar range, in particular against the A3 receptor. Thus, the 1-benzyl-3-propyl-1H,3H-pyrido[2,1-f]purine-2,4-dione derivative 6, which can be considered a lead compound in this series, exhibited a Ki value of 4.0 ± 0.3 nM against the hA3 receptor. Because xanthine derivatives have traditionally been considered poor A3 antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration.

A new and efficient one-pot synthesis of pyrido[2,1-f]purine-2,4-diones starting from 6-aminouracil derivatives

A convenient synthesis of pyrido[2,1-f]purine-2,4-diones is described by reaction of 6-aminouracil derivatives with N-bromosuccinimide (NBS) followed by in situ reaction with pyridine or 4-substituted pyridines. A detailed study of the reaction conditions has been performed and a mechanism involving a 5,5-dibromo derivative is proposed.