Ipatova DA, Ikonnikova VA, Kungurtsev KD
… +9 more, Kashapov AI, Shafikov RR, Kartsev VG, Glushkov AK, Myasnyanko IN, Baranov MS, Mikhaylov AA, Dontsova OA, Skvortsov DA
ACS Med Chem Lett
· 2026 May · PMID 42157835
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The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the "privileged scaffold" of the chroman-4-one with rigid spirocycli...The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the "privileged scaffold" of the chroman-4-one with rigid spirocyclic structures offers a strategy for modulating the specificity of action. A collection of 28 spirocyclohexane-chroman-4-one derivatives was screened using fluorescence cell coculture test, and compound was selective in the breast cancer model. Structure-activity relationship analysis was performed within three rounds of optimization with rational synthesis of derivatives. Reduction of the carbonyl group to hydroxyl and incorporation of a dioxolane group into the spirocyclohexane ring reduced toxicity toward noncancerous VA13 and MCF10A cells. The lead compound with this elaborated structure exhibited cytotoxicity against MCF7 cells (IC ≈ 3.8 μM) and remained significantly less cytotoxic to both noncancerous cells. It highlights the potential of spirocyclic-fused chroman-4-ones as selective cytotoxic agents through rigidifying the molecular scaffold and precisely tuning the functional group positioning.
Romanowska J, Wawrzyniak D, Szymanska-Michalak A
… +6 more, Framski G, Pawlowicz-Perczak A, Sobkowski M, Stawinski J, Rolle K, Kraszewski A
ACS Med Chem Lett
· 2026 May · PMID 42157833
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Three series of 5-fluoro-2'-deoxyuridine (FdU) nucleotide analogues were studied as potential antiglioma pronucleotides. The 5'-OH position was esterified with H-phosphonate, phosphate, and acylphosphate residues, all of...Three series of 5-fluoro-2'-deoxyuridine (FdU) nucleotide analogues were studied as potential antiglioma pronucleotides. The 5'-OH position was esterified with H-phosphonate, phosphate, and acylphosphate residues, all of which had negative charges. Additionally, some carried protecting groups of varying lipophilicity at the 3'-OH position. The acylphosphate moiety also contained different hydrocarbon substituents. The amphiphilic nature of these compounds should render them water-soluble and facilitate their permeation through the cell membranes. Inside the cell, they were expected to be converted to 5-fluoro-2'-deoxyuridine 5'-phosphate, a highly effective inhibitor of thymidylate synthetase. Two of the studied new FdU derivatives exhibited promising antiproliferative activity against the glioblastoma multiforme T98G cell line, an order of magnitude better than that of the parent nucleoside.
Manchoju A, Duffy NM, Zelli R
… +11 more, Eymard C, Gallant M, Genieyz A, Labbé MO, Lussier T, Michaud G, Théroux L, Dostie S, Black WC, Guindon Y, Prévost M
ACS Med Chem Lett
· 2026 Jan · PMID 41531959
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We report findings on a novel family of nucleotide analogues with selective inhibitory activity against DNA polymerase theta (Polθ), a key enzyme in the theta-mediated end joining pathway and a critical player in synthet...We report findings on a novel family of nucleotide analogues with selective inhibitory activity against DNA polymerase theta (Polθ), a key enzyme in the theta-mediated end joining pathway and a critical player in synthetic lethality-based cancer therapies. Polθ's intrinsically low fidelity, which contributes to genomic instability in homologous recombination-deficient tumors, was probed for selective targeting by these analogues. The newly identified compounds feature an all-carbon stereogenic quaternary center at either the C3' or C2' position of the furanoside ring, a structural modification that has already demonstrated potential in antiviral, anticancer, and cardioprotective applications. Biochemical assays suggest these analogues exploit Polθ's unique active site architecture, offering a possible direction for overcoming PARP inhibitor resistance and enhancing personalized cancer treatment strategies.
Tantawi H, Mochirian P, Truong M
… +14 more, Beauregard J, Collins L, Kanaan G, Komati H, Leblanc L, Maharsy W, Manchoju A, Simard R, Tambutet G, Teran C, Dostie S, Prévost M, Nemer M, Guindon Y
ACS Med Chem Lett
· 2025 Sep · PMID 40959263
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A novel nucleoside analogue, LCB-2151, has been developed to induce cell death in -mutated pancreatic human cancer cell lines, which exhibit partial resistance to gemcitabine, a widely used anticancer drug. LCB-2151 disr...A novel nucleoside analogue, LCB-2151, has been developed to induce cell death in -mutated pancreatic human cancer cell lines, which exhibit partial resistance to gemcitabine, a widely used anticancer drug. LCB-2151 disrupts the two primary sources of ATP production, namely, glycolysis and mitochondrial oxidative phosphorylation, reducing the bioenergetic capacity of these cells and inducing the formation of reactive oxygen species. Metabolomics and mitochondrial respiration analyses reveal that LCB-2151 inhibits key enzymes in glycolysis, the TCA cycle, and fatty acid β-oxidation. These findings highlight a coordinated mechanism driving bioenergetic disruption and cell death.
Bakhoda AG, Pearson TD, Gao ZG
… +12 more, O'Conor KA, Eisenberg SM, Kelleher AC, Kang Y, Liow JS, Choi JY, Kim W, Seo J, Freaney ML, Jacobson KA, Volkow ND, Kim SW
ACS Med Chem Lett
· 2025 Jul · PMID 40666472
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Several adenosine A receptor (AR) radiotracers for positron emission tomography (PET) have been developed to study their neuromodulatory functions and role in brain disorders. While two xanthine-based radiotracers ([C]-M...Several adenosine A receptor (AR) radiotracers for positron emission tomography (PET) have been developed to study their neuromodulatory functions and role in brain disorders. While two xanthine-based radiotracers ([C]-MPDX and [F]-CPFPX) have been used in humans, we aimed to improve the metabolic stability and specific binding. Guided by structure-activity relationship (SAR) studies, 10 derivatives were synthesized with binding affinities up to 0.12 nM. Three subnanomolar candidates (, , ) were radiolabeled with C-11 ( = 20.4 min) for evaluation using in vivo PET imaging and ex vivo rodent brain biodistribution. Although [C] demonstrated a higher blood-brain barrier (BBB) permeability, negligible in vivo specific binding was observed. Ex vivo studies indicated that all three compounds are substrates for brain efflux pumps. Despite optimized affinity, BBB permeability and in vivo binding specificity remain challenges. These findings inform development of nonxanthine AR radiotracers and highly potent CNS AR drugs.
ACS Med Chem Lett
· 2025 Jun · PMID 40529076
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Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase with enzymatic and scaffolding functions, composed of a FERM domain, kinase domain, proline-rich regions, and a FAT domain. It interacts with over 50 proteins...Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase with enzymatic and scaffolding functions, composed of a FERM domain, kinase domain, proline-rich regions, and a FAT domain. It interacts with over 50 proteins and plays a key role in cancer progression, metastasis, and recurrence. Although eight FAK inhibitors have entered clinical trials, they primarily block kinase activity and fail to disrupt scaffolding functions. PROTAC technology offers a novel strategy by degrading the entire FAK protein, eliminating both functions. Several FAK-targeting PROTACs have been developed with promising results. Given FAK's critical role in tumor malignancy, combination therapiessuch as dual-target degradation or inhibitor-degrader strategiesmay provide enhanced anticancer efficacy.
Kim G, Lee G, Jarhad DB
… +5 more, Gao ZG, Kim SW, Joung M, Jacobson KA, Jeong LS
ACS Med Chem Lett
· 2025 May · PMID 40365401
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Numerous adenosine receptor (AR) ligands have been synthesized over many years, but the development of 2,8-disubstituted nucleoside derivatives was limited due to the lack of efficient synthetic methods. Leveraging Pd ca...Numerous adenosine receptor (AR) ligands have been synthesized over many years, but the development of 2,8-disubstituted nucleoside derivatives was limited due to the lack of efficient synthetic methods. Leveraging Pd catalyst-controlled regioselective coupling, we embarked on structure-activity relationship (SAR) analyses at the C8 position. Our SAR studies revealed that an aliphatic alkyne chain of specific length, such as 1-hexyne, at the C8 position is ideally suited for hAAR interaction. A computational docking study revealed that the π-π interaction between His95 and C8-aromatic alkyne could induce an active conformation of hAAR. Notably, compound demonstrated exceptional potency and selectivity at hAAR ( = 3.0 ± 0.5 nM), acting as the first 2,8-disubstituted nucleoside AAR partial agonist. It underscores the strategic importance of C8 position modifications in modulating AR activity and function, paving the way for novel therapeutic agents targeting AR-mediated diseases.
Grabarek M, Tabor W, Krzyżek P
… +3 more, Grabowiecka A, Berlicki Ł, Mucha A
ACS Med Chem Lett
· 2025 Apr · PMID 40236561
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Inspired by the recognized activity of Ebselen against urease, we optimized the structure of 1,2-benzisoselenazol-3(2)-one to provide potent inhibitors of ureolysis in cells. To achieve this goal, we combined the elonga...Inspired by the recognized activity of Ebselen against urease, we optimized the structure of 1,2-benzisoselenazol-3(2)-one to provide potent inhibitors of ureolysis in cells. To achieve this goal, we combined the elongation of the N-substituent of Ebselen from phenyl to benzyl with halogenation of the aromatic fragment. The modifications implemented provided compounds with activities that were several times better compared to that of the lead compound. In particular, 3-fluoro-4-trifluoromethyl and 2-chloro-5-fluoro derivatives of -benzyl-1,2-benzisoselenazol-3(2)-one achieved a remarkable antiureolytic effect in live cells (IC < 100 nM) that outperformed the data reported so far. This activity was reflected in the antiurease potential measured for the model enzyme, with the highest affinity observed for 2-chloro-5-fluoro and 2,4-dichloro derivatives ( < 0.6 nM). The best inhibitor demonstrated considerable antibacterial properties on a multidrug-resistant clinical isolate in additive combination with clarithromycin (MIC = 0.073 μg/mL).
Joyal M, Simard RD, Maharsy W
… +3 more, Prévost M, Nemer M, Guindon Y
ACS Med Chem Lett
· 2025 Jan · PMID 39811128
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Inflammatory disorders, such as sepsis, pancreatitis, and severe COVID-19, often cause immune dysfunction and high mortality. These conditions trigger excessive immune cell influx, leading to cytokine storms, organ damag...Inflammatory disorders, such as sepsis, pancreatitis, and severe COVID-19, often cause immune dysfunction and high mortality. These conditions trigger excessive immune cell influx, leading to cytokine storms, organ damage, and compensatory immune suppression that results in immunoparalysis, organ dysfunction, and reinfection. Controlled and reversible immunosuppression limiting immune cell recruitment to inflammation sites could reduce hyperinflammation and prevent immune exhaustion. PSGL-1 on leukocytes binds to vascular P- and E-selectins via its sialyl Lewis pharmacophore, triggering key features of systemic inflammatory response syndrome and sepsis. We report the discovery of two immunomodulators, sialyl Lewis glycomimetics ( and ), with a tetrazole carboxyl bioisostere of , which binds P- and E-selectin and blocks their interaction with PSGL-1. In an hyperinflammation model, they reduced immune cell recruitment, evidenced by decreased neutrophils, CD11b+, monocytes/macrophages, and PSGL-1-positive cells at various time points. These glycomimetics may be promising leads for managing the systemic inflammatory response syndrome.
Kim M, Choi H, Nayak A
… +5 more, Tripathi SK, Aswar VR, Gaikwad VB, Jacobson KA, Jeong LS
ACS Med Chem Lett
· 2024 Sep · PMID 39420956
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This study explored the impact of structural modifications on truncated 4'-selenonucleosides as ligands for the A adenosine receptor (AR). We synthesized and evaluated a series of these compounds for their binding affini...This study explored the impact of structural modifications on truncated 4'-selenonucleosides as ligands for the A adenosine receptor (AR). We synthesized and evaluated a series of these compounds for their binding affinities, functional activities, and structural interactions by using computational modeling. The SAR study revealed that all compounds exhibited selective and notable hAAR binding, among which ( = 5.2 nM) and ( = 5.7 nM) were found as the best binding compounds. The representative -cyclopropyl compound was found to be a partial agonist, contrasting with the antagonist profiles of truncated 4'-oxo and 4'-thionucleosides. Computational docking highlighted 's unique interaction with Thr94 at the AAR binding site. This research not only advances our understanding of AAR ligand interactions but also highlights the potential of truncated 4'-selenonucleosides as effective AAR modulators.
Mandal S, Suseela YV, Samanta S
… +3 more, Vileno B, Faller P, Govindaraju T
ACS Med Chem Lett
· 2024 Aug · PMID 39140073
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Alzheimer's disease is a progressive neurodegenerative disorder that significantly contributes to dementia. The lack of effective therapeutic interventions presents a significant challenge to global health. We have devel...Alzheimer's disease is a progressive neurodegenerative disorder that significantly contributes to dementia. The lack of effective therapeutic interventions presents a significant challenge to global health. We have developed a set of short peptides (PN) conjugated with a dual-functional fluorophoric amino acid (N). The lead peptide, P2N, displays a high affinity for Cu, maintaining the metal ion in a redox-inactive state. This mitigates the cytotoxicity generated by reactive oxygen species (ROS), which are produced by Cu under the reductive conditions of Asc and Aβ or Aβ. Furthermore, P2N inhibits both Cu-dependent and -independent fibrillation of Aβ, along with the subsequent toxicity induced by Aβ. In addition, P2N exhibits inhibitory effects on the production of lipopolysaccharide (LPS)-induced ROS and reactive nitrogen species (RNS) in microglial cells. In vitro and cellular studies indicate that P2N could significantly reduce Aβ-Cu-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer's disease.
Maruyama T, Takahashi Y, Hiro K
… +5 more, Murase K, Kojima H, Okabe T, Yamauchi Y, Sato R
ACS Med Chem Lett
· 2024 May · PMID 38994455
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Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated meta...Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated metabolic diseases make it a potential therapeutic target. However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors. Here, we aimed to identify small-molecule compounds that directly bind to SREBP-1 using the recombinant N-terminal region of SREBP-1a, which is required for its transcriptional activity. A high-throughput screening campaign was conducted using a thermal shift assay and surface plasmon resonance assay to evaluate the compound affinity and specificity, which resulted in the identification of two compounds. Future analysis of their structure-activity relationships may lead to the development of specific SREBP-1 inhibitors, thereby potentially validating SREBP-1 as a therapeutic target for obesity and resultant atherosclerotic diseases.
Szustak M, Korkus E, Madaj R
… +9 more, Chworos A, Dąbrowski G, Czaplicki S, Tabandeh E, Maciejewska G, Koziołkiewicz M, Konopka I, Gliszczyńska A, Gendaszewska-Darmach E
ACS Med Chem Lett
· 2024 Feb · PMID 38352825
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Among lipids, lysophosphatidylcholines (LPCs) with various fatty acyl chains have been identified as potential agonists of G protein-coupled receptors (GPCRs). Recently, targeting GPCRs has been switched to diabetes and...Among lipids, lysophosphatidylcholines (LPCs) with various fatty acyl chains have been identified as potential agonists of G protein-coupled receptors (GPCRs). Recently, targeting GPCRs has been switched to diabetes and obesity. Concomitantly, our last findings indicate the insulin secretagogue properties of and palmitoleic acid (16:1, n-7) resulting from GPCR activation, however, associated with different signaling pathways. We here report the synthesis of LPCs bearing two geometrical isomers of palmitoleic acids and investigation of their impact on human pancreatic β cells viability, insulin secretion, and activation of four GPCRs previously demonstrated to be targeted by free fatty acids and LPCs. Moreover, molecular modeling was exploited to investigate the probable binding sites of tested ligands and calculate their affinity toward GPR40, GPR55, GPR119, and GPR120 receptors.
Krols S, Matteucci F, Van Hecke K
… +3 more, Caljon G, Jacobson KA, Van Calenbergh S
ACS Med Chem Lett
· 2024 Jan · PMID 38229744
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Various purine-based nucleoside analogues have demonstrated unexpected affinity for nonpurinergic G protein-coupled receptors (GPCRs), such as opioid and serotonin receptors. In this work, we synthesized a small library...Various purine-based nucleoside analogues have demonstrated unexpected affinity for nonpurinergic G protein-coupled receptors (GPCRs), such as opioid and serotonin receptors. In this work, we synthesized a small library of new 7-deazaadenosine and pyrazolo[3,4-]pyrimidine riboside analogues, featuring dual C7 and modifications and assessed their affinity for various GPCRs. During the course of the synthesis of 7-ethynyl pyrazolo[3,4-]pyrimidine ribosides, we observed the formation of an unprecedented tricyclic nucleobase, formed via a 6- ring closure. The synthesis of this tricyclic nucleoside was optimized, and the substrate scope for such cyclization was further explored because it might avail further exploration in the nucleoside field. From displacement experiments on a panel of GPCRs and transporters, combining C7 and modifications afforded noncytotoxic nucleosides with micromolar and submicromolar affinity for different GPCRs, such as the 5-hydroxytryptamine (5-HT), κ-opioid (KOR), and σ receptor. These results corroborate that the novel nucleoside analogues reported here are potentially useful starting points for the further development of modulators of GPCRs and transmembrane proteins.
Oliva P, Suresh RR, Pasquini S
… +9 more, Salmaso V, Will EJ, Tosh DK, Gao ZG, Liu N, Gavrilova O, Vincenzi F, Varani K, Jacobson KA
ACS Med Chem Lett
· 2023 Dec · PMID 38116442
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A adenosine receptor (AAR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure-activity relationship of 5-arylethynyl aminothiophenes as AA...A adenosine receptor (AAR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure-activity relationship of 5-arylethynyl aminothiophenes as AAR positive allosteric modulators (PAMs). The derivatives were compared in binding and functional assays at the human AAR, indicating that some fluoro-substituted analogues have enhanced PAM activity. We identified substitution of the terminal phenyl ring in (2-F-Ph), (3,4-F-Ph, MRS7935), and (2-CF-Ph) as particularly enhancing the PAM activity. was also shown to act as an A ago-PAM with EC ≈ 2 μM, without activity (30 μM) at other ARs. Molecular modeling indicated that both the 5-arylethynyl and the 4-neopentyl groups are located in a region outside the receptor transmembrane helix bundle that is in contact with the phospholipid bilayer, consistent with the preference for nonpolar substitution of the aryl moiety. Although they are hydrophobic, these PAMs could provide potential drug candidate molecules for engaging protective AARs.
ACS Med Chem Lett
· 2023 Jan · PMID 36655120
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In this article the physicochemical and biological properties of sequence-related G-quadruplex forming oligonucleotides in RNA and DNA series are analyzed and compared. The intermolecular G-quadruplexes vary in loop leng...In this article the physicochemical and biological properties of sequence-related G-quadruplex forming oligonucleotides in RNA and DNA series are analyzed and compared. The intermolecular G-quadruplexes vary in loop length, number of G-tetrads and homogeneity of the core. Our studies show that even slight variations in sequence initiate certain changes of G-quadruplex properties. DNA G-quadruplexes are less thermally stable than their RNA counterparts, more topologically diversified and are better candidates as inhibitors of cancer cells proliferation. The most efficient antiproliferative activity within the studied group of molecules was observed for two DNA G-quadruplexes with unperturbed core and lower content of thymidine residues within the loops leading to reduction of cells viability up to 65% and 33% for and cell lines, respectively.
Kondratov IS, Moroz YS, Grygorenko OO
… +1 more, Tolmachev AA
ACS Med Chem Lett
· 2022 Jul · PMID 35859862
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Ukrainian companies occupy an important niche in the global drug discovery process; however, before the Russian invasion, the role of Ukraine was not obvious. The biggest Ukrainian fine chemical supplier, Enamine Ltd, ha...Ukrainian companies occupy an important niche in the global drug discovery process; however, before the Russian invasion, the role of Ukraine was not obvious. The biggest Ukrainian fine chemical supplier, Enamine Ltd, had to stop operation for more than a month, which significantly affected various early-stage drug discovery projects. The role of Enamine in drug discovery and the company's past and future in the context of the Russian invasion are described in this Viewpoint.
Suresh RR, Gao ZG, Salmaso V
… +5 more, Chen E, Campbell RG, Poe RB, Liston TE, Jacobson KA
ACS Med Chem Lett
· 2022 Apr · PMID 35450351
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The A adenosine receptor (AAR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non...The A adenosine receptor (AAR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non-nucleoside antagonists are limited in selectivity to primate species. We have explored the structure-activity relationship of a previously reported AAR antagonist DPTN (-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide) for radiolabeling, including 3-halo derivatives (3-iodo, MRS7907), and characterized as a high -affinity radioligand [H]MRS7799. AAR values were (nM): 0.55 (human), 3.74 (mouse), and 2.80 (rat). An extended methyl acrylate (MRS8074, ) maintained higher affinity (18.9 nM) than a 3-((5-chlorothiophen-2-yl)ethynyl) derivative . Compound had an excellent brain distribution in rats (brain/plasma ratio ∼1). Receptor docking predicted its orthosteric site binding by engaging residues that were previously found to be essential for AR binding. Thus the new radioligand promises to be a useful species-general antagonist tracer for receptor characterization and drug discovery.
Li S, Zhang T, Zhu SJ
… +11 more, Lei C, Lai M, Peng L, Tong L, Pang Z, Lu X, Ding J, Ren X, Yun CH, Xie H, Ding K
ACS Med Chem Lett
· 2022 Feb · PMID 35178175
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A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values o...A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. also demonstrated promising EGFR mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR with a close derivative was solved to provide insight on the inhibitor's binding mode. Moreover, compound was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.
Tosh DK, Brackett CM, Jung YH
… +4 more, Gao ZG, Banerjee M, Blagg BSJ, Jacobson KA
ACS Med Chem Lett
· 2021 Mar · PMID 33738064
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The heat shock protein 90 kDa (Hsp90) family of chaperones is highly sought-after for the treatment of cancer and neurodegenerative diseases. Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum localized is...The heat shock protein 90 kDa (Hsp90) family of chaperones is highly sought-after for the treatment of cancer and neurodegenerative diseases. Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum localized isoform that is responsible for the maturation of proteins involved in cell adhesion and the immune response, including Toll-like receptors, immunoglobulins, and integrins. Consequently, Grp94 has been implicated in many different diseases including cancer metastasis, glaucoma, and viral infection. 5'-(-Ethylcarboxamido)adenosine (NECA) was identified from a high-throughput screen as one of the first molecules to exhibit isoform selectivity toward Grp94, with the ethyl group projecting into a unique pocket within the ATP binding site of Grp94. This pocket has since been exploited by several groups to develop Grp94 selective inhibitors. Despite success in the development of other classes of inhibitors, relatively little work has been done to further develop inhibitors with the NECA scaffold. Unfortunately, NECA is also a potent adenosine receptor agonist, which is likely to confound any biological activity. Therefore, structure-activity relationship studies were performed on the NECA scaffold leading to the discovery of several molecules that displayed similar selectivity and affinity as the parent compound.