Discovery and optimization of potent and selective functional antagonists of the human adenosine A2B receptor

Bedford, Simon T.; Benwell, Karen; Brooks, Teresa; Chen, I‐Jen; Comer, Mike; Dugdale, Sarah; Haymes, Tim; Jordan, Allan M.; Kennett, Guy A.; Knight, Anthony; Klenke, Burkhard; LeStrat, Loic; Merrett, Angela; Misra, Anil Kumar; Lightowler, S.; Padfield, Anthony; Poullennec, Karine G.; Reece, Mark; Simmonite, Heather; Wong, Melanie; Yule, Ian A.

doi:10.1016/j.bmcl.2009.08.040

Cited by 11 publications

(7 citation statements)

References 17 publications

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“…A novel class of thienopyrimidine scaffolded antagonists of the human adenosine A 2B AR was proposed by Bedford et al [69]: among these low molecular weight derivatives, compound 47 ( Table 9) demonstrated strong antagonism to the A 2B AR despite its limited aqueous solubility; furthermore, its poor oral bio-availability and short half-life revealed a preliminary pharmacokinetic profile suitable for either inhaled or systemic routes of administration.…”

Section: Non-xanthinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

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Section: Non-xanthinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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“…From a structural point of view, A 2B AR antagonists can be subdivided into two classes, namely, xanthines and nonxanthine heterocyclic derivatives (Figure ). − The discovery of the (nonselective) micromolar antagonistic profile of the natural alkaloids caffeine and theophylline motivated the synthesis of thousands of xanthine congeners . The systematic modification at positions 1, 3, and 8 of the xanthine scaffold enabled the development of potent and selective A 2B AR ligands (Figure , compounds 2 – 5 ). − Similarly, pharmacomodulation of the heterobicyclic core at the physiological agonist (adenosine) provided adenine derivatives that exhibit attractive A 2B AR profiles.…”

Section: Introductionmentioning

confidence: 99%

“…However, while these derivatives provided valuable compounds that enabled an exhaustive exploration of the structure, signaling, and (patho)physiological roles of A 2B AR, a major drawback of xanthine derivatives and adenine-related AR ligands is their generally low water solubility. Accordingly, novel families of heterocyclic scaffolds have progressively enriched the compendium of A 2B AR antagonists, − usually providing novel topologies, physicochemical features, and alternative binding modes. Although the vast majority of known A 2B AR antagonists are planar derivatives, some novel ligands bearing a chiral center within the central heterocyclic framework have recently been discovered. − These novel series provided potent and highly selective A 2B AR antagonists that enable the establishment of stereoselective ligand–target interactions, thus offering the first examples of stereospecific recognition at A 2B AR. , …”

Section: Introductionmentioning

confidence: 99%

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists

Mallo-Abreu¹,

Prieto-Díaz²,

Jespers

et al. 2020

J. Med. Chem.

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A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A 2B AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4dihydrobenzo [4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (K i < 30 nM) and exquisite selectivity. The structure−activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA 2B AR and the eutomer of the most attractive novel antagonist (S)-18g (K i = 3.66 nM) was validated.

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“…Initially 2,4,6-trichloropyrimidine was reacted with o , o -difluorobenzaldehyde and sodium hydride using N,N′ -dimethylbenzimidazolium iodide as a catalyst (Scheme 1). 30,31 Two dichloropyrimidine regioisomers were isolated for each aldehyde with the carbonyl group either in the primarily desired position 4 (compounds 1 , 2 ) or in position 2 ( 3, 4 ). The next step in the synthetic sequence was nucleophilic substitution of one chlorine atom by ammonia.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and anti-human immunodeficiency virus activity of substituted (o,o-difluorophenyl)-linked-pyrimidines as potent non‐nucleoside reverse transcriptase inhibitors

Čechová

Dejmek

Baszczyňski

et al. 2019

Antivir Chem Chemother

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With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o,o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o,o-difluoro-p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.

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Discovery and optimization of potent and selective functional antagonists of the human adenosine A2B receptor

Cited by 11 publications

References 17 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists

Synthesis and anti-human immunodeficiency virus activity of substituted (o,o-difluorophenyl)-linked-pyrimidines as potent non‐nucleoside reverse transcriptase inhibitors

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Discovery and optimization of potent and selective functional antagonists of the human adenosine A2B receptor

Cited by 11 publications

References 17 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists

Synthesis and anti-human immunodeficiency virus activity of substituted (o,o-difluorophenyl)-linked-pyrimidines as potent non‐nucleoside reverse transcriptase inhibitors

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Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists