Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Abstract

Adenosine, an endogenous purine nucleoside, modulates a variety of physiological functions in various organs and tissues, and interacts with four specific G-protein-coupled receptor subtypes (GPCRs), classified as A 1 , A 2A , A 2B , and A 3 .1,2) All four receptors are coupled via G proteins to the adenylate cyclase-cAMP signal transduction pathway. Activation of A 1 and A 3 receptors inhibits adenylate cyclase through G i coupling, while activation of A 2A and A 2B receptors stimulates adenylate cyclase through G s coupling.3) In particular, the adenosine A 3 receptor (A 3 AR) is distributed in different organs (lung, liver, kidney, heart and brain), 4) and the potential therapeutic applications of antagonizing this receptor are proposed to be useful for the treatment of inflammation, 5) myocardial and brain ischemia, [6][7][8] and cancer. 27,28) have been reported as new hA 3 AR antagonists. Although these antagonists showed strong hA 3 AR antagonistic activity and good selectivity against other adenosine receptor subtypes, they were found to be weak or ineffective against rat A 3 AR (rA 3 AR), 1,11,12,15,28,29) and could therefore not be evaluated in rat in vivo models. The homology of A 3 AR among several species was reported and the only 72% homology between human and rat A 3 AR was one reason for species differences.28) As selective hA 3 AR antagonists that showed moderate affinity to rA 3 AR, only MRS 1191 14) and MRS 1523 15) (K i ϭ1.42, 0.113 mM, respectively) have been reported, but these activities seemed to be insufficient for evaluation in rat models. Thus, A 3 AR antagonists which show equipotent affinity and selectivity in different species have been desired for pharmacological probes on animal models, and the evaluation and selection of new drugs in preclinical phase candidates is likely to be easier.Our focus on an anti-asthmatic research program prompted us to evaluate the potential of A 3 AR antagonist as a therapeutic target. From high throughput screening, 4-phenyl-5-pyridyl-1,3-thiazole derivative 7a was identified as the preferable lead compound. We have already reported 1,3-thiazole derivatives as p38 MAP kinase inhibitors. 30,31) These compounds were bound at the ATP binding site of the kinase, and ATP is an adenosine-related compound. We therefore focused our attention on compound 7a and investigated further. In the in vitro binding assay, compound 7a showed strong hA 3 AR antagonistic activity (K i ϭ0.16 nM) and good hA 3 AR selectivity, as shown in Fig. 1. Moreover, the rA 3 AR antagonistic activity of this compound was moderate (K i ϭ23 nM). To evaluate the efficacy of the rat asthma model, improvement of the rA 3 AR antagonistic activity of 7a was critical. In the present paper, we report the discovery of a series of 2-acylamino-4-phenyl-5-pyridyl-1,3-thiazole derivatives as novel and potent antagonists against human and rat A 3 AR through structural modification based on screening hit 7a. ChemistryThe general approach for the several 4,5-disubstituted 2-acylamino-1,3-thiazoles 7 ...

Fragment Screening at Adenosine-A3 Receptors in Living Cells Using a Fluorescence-Based Binding Assay

“…Of the 18 non-ring fused thiazole variants, our assay identified five as hits (Figure S4A). However, modeling studies performed to-date suggest that the key receptor-ligand interactions are achieved through the substituents present on the heterocyclic ring rather the thiadiazole itself (Miwatashi et al., 2008). One could therefore envisage that with such simple fragments, binding via alternative geometries is entirely probable and it was encouraging that the more highly decorated heteroaryl-aryl linked hit fragments did indeed possess the superior binding affinities; possible by virtue of additional points of contact with the receptor binding site.…”

Pharmacological characterisation of novel adenosine A3 receptor antagonists

“…MRS 1220 N-(9-chloro-2-furan-2-yl- [1,2,4]triazolo [1,5-c]quinazolin-5-yl)-2-phenylacetamide NECA (2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-N-ethyl-3,4-dihydroxyoxolane- The adenosine A 3 receptor (A 3 R), belongs to a family of four adenosine receptor (AR) subtypes (A 1 R, A 2A R, A 2B R and A 3 R), and is involved in a range of pathologies including cardiovascular, neurological and tumour-related diseases. Unsurprisingly therefore, A 3 R is a pharmaceutical target.…”

“…Interestingly, the A 3 R has been described as enigmatic, whereby many of the effects attributed to A 3 Rs are contradictory 1 . Despite this, A 3 R antagonists having been described as potential treatments of asthma, chronic obstructive pulmonary disease (COPD) and glaucoma 2,3 , continuous research into antagonists at the A 3 R are warranted. It has also been suggested that the A 3 R is over expressed in various tumour cells suggesting it may be a viable drug target against cancer proliferation [4][5][6] .…”

“…IB-MECA stimulated cAMP inhibition at WT A 3 R: activity of N-(9-chloro-2-furan-2-yl-[1,2,4] triazolo[1,5-c]quinazolin-5-yl)-2-phenylacetamide (MRS 1220) and potential antagonists. Flp-In-CHO cells (2000 cells/well) stably expressing WT A 3 R were exposed to forskolin 10 μM, IB-MECA and test compound/MRS 1220/DMSO control for 30 min and cAMP accumulation detected.…”

Effects of etifoxine: Chemoreactome simulation

“…Заметим, что селек-тивные антагонисты рецепторов А3 аденозина исследуются как потенци-альные противовоспалительные сред-ства [20]. Эти выводы, следующие из результатов хемореактомного анали-за, подтверждаются установленным противовоспалительным действием этифоксина при экспериментальном аутоиммунном энцефалите [21] и на модели отека мозга [22].…”