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Covalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we aimed to develop a covalent antagonist of CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a therapeutic target in inflammation and immuno-oncology. Based on a known intracellularly binding CCR2 antagonist, several covalent derivatives were synthesized and characterized by radioligand binding and functional assays. These studies revealed compound 14 as an intracellular covalent ligand for CCR2. In silico modeling followed by site-directed mutagenesis confirmed that 14 forms a covalent bond with one of three proximal cysteine residues, which can be engaged interchangeably. To our knowledge, compound 14 represents the first covalent ligand reported for CCR2. Due to its unique properties, it may represent a promising tool for ongoing and future studies of CCR2 pharmacology.

The rearrangement of 2,5-bis(silylated)-N-Boc pyrroles in their 2,4-isomers processed under mild acidic conditions is reported. The transformation mechanism is demonstrated based on the literature as well as experiments.

The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N, N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5'-substituted amiloride derivatives as hA2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [3H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([3H]ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA2AAR. 4-Ethoxyphenethyl-substituted amiloride 12l was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site. [ABSTRACT FROM AUTHOR]

We report the synthesis and evaluationof previously unreported4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosineA1receptor (hA1AR) agonists with tunable bindingkinetics, this without affecting their nanomolar affinity for thetarget receptor. They show a very diverse range of kinetic profiles(from 1 min (compound 52) to 1 h (compound 43)), and their structure–affinity relationships (SAR) and structure–kineticsrelationships (SKR) were established. When put in perspective withthe increasing importance of binding kinetics in drug discovery, theseresults bring new evidence of the consequences of affinity-only drivenselection of drug candidates, that is, the potential elimination ofslightly less active compounds that may display preferable bindingkinetics. [ABSTRACT FROM AUTHOR]

Cardiotoxicityis a side effect that plagues modern drug design and is very oftendue to the off-target blockade of the human ether-à-go-go relatedgene (hERG) potassium channel. To better understand the structuraldeterminants of this blockade, we designed and synthesized a seriesof 40 derivatives of clofilium, a class III antiarrhythmic agent.These were evaluated in radioligand binding and patch-clamp assaysto establish structure–affinity relationships (SAR) for thispotassium channel. Efforts were especially focused on studying theinfluence of the structural rigidity and the nature of the linkerscomposing the clofilium scaffold. It was shown that introducing triplebonds and oxygen atoms in the n-butyl linker of themolecule greatly reduced affinity without significantly modifyingthe pKaof the essential basic nitrogen.These findings could prove useful in the first stages of drug discoveryas a systematic way of reducing the risk of hERG K+channelblockade-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Drug-inducedblockade of the human ether-a-go-go-related gene K+channel(hERG) represents one of the major antitarget concernsin pharmaceutical industry. SAR studies of this ion channel have shedlight on the structural requirements for hERG interaction but mostimportantly may reveal drug design principles to reduce hERG affinity.In the present study, a novel library of neutral and positively chargedheteroaromatic derivatives of the class III antiarrhythmic agent dofetilidewas synthesized and assessed for hERG affinity in radioligand bindingand manual patch clamp assays. Structural modifications of the pyridinemoiety, side chain, and peripheral aromatic moieties were evaluated,thereby revealing approaches for reducing hERG binding affinity. Inparticular, we found that the extra rigidity imposed close to thepositively charged pyridine moiety can be very efficient in decreasinghERG affinity. [ABSTRACT FROM AUTHOR]

The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5'-substituted amiloride derivatives as hA2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [(3)H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([(3)H]ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA2AAR. 4-Ethoxyphenethyl-substituted amiloride 12l was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site.

The asymmetric synthesis of (-)-swainsonine and (-)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,β-dialkoxy N-tert-butanesulfinylimines derived from d-erythronolactone.