Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development

Adenosine receptors (ARs) function in the body’s response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A1AR activation or increasing the blood supply to heart muscle by the A2AAR. Moreover, exogenous AR agonists, antagonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral agonists, adenosine and Regadenoson, are the only AR agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR agonists for treating inflammation, pain, cancer, non-alcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A3AR agonists are ongoing

Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y 6 Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modifications †

The P2Y6 receptor is a cytoprotective G protein-coupled receptor (GPCR) activated by UDP (EC50, 0.30 μM). We compared and combined modifications to enhance P2Y6 receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as α,β-methylene and extension of the terminal phosphate group into γ-esters of UTP analogues. The conformationally constrained (S)-methanocarba UDP is a full agonist (EC50 0.042 μM). 4-Methoxyimino modification of pyrimidine enhanced P2Y6, preserved P2Y2 and P2Y4, and abolished P2Y14 receptor potency, in the appropriate nucleotide. N4-Benzyloxy-CDP (15, MRS2964) and N4-methoxy-Cp3U (23, MRS2957) were potent, selective P2Y6 receptor agonists (EC50 0.026 μM and 0.012 μM, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-γ-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y6 receptor potency, but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N4-methoxy-cytidine 5′-triphospho-γ-[1]glucose were active (EC50 of 2.47 μM and 0.18 μM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y6 receptor agonists may be enhanced by modest structural changes

Polyamidoamine (PAMAM) Dendrimer Conjugates of “Clickable” Agonists of the A 3 Adenosine Receptor and Coactivation of the P2Y 14 Receptor by a Tethered Nucleotide

We previously synthesized a series of potent and selective A3 adenosine receptor (AR) agonists (North-methanocarba nucleoside 5′-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed “click” chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. A3AR activation was preserved in these multivalent conjugates, which bound with apparent Ki 0.1–0.3 nM. They were substituted with nucleoside moieties, solely or in combination with water-solubilizing carboxylic acid groups derived from hexynoic acid. A comparison with various amide-linked dendrimers showed that triazole-linked conjugates displayed selectivity and enhanced A3AR affinity. We prepared a PAMAM dendrimer containing equiproportioned peripheral azido and amino groups for conjugation of multiple ligands. A bifunctional conjugate activated both A3 and P2Y14 receptors (via amide-linked uridine-5′-diphosphoglucuronic acid), with selectivity in comparison to other ARs and P2Y receptors. This is the first example of targeting two different GPCRs with the same dendrimer conjugate, which is intended for activation of heteromeric GPCR aggregates. Synergistic effects of activating multiple GPCRs with a single dendrimer conjugate might be useful in disease treatment

Structure-Activity Analysis of Biased Agonism at the Human Adenosine A 3 Receptor s

ABSTRACT Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A 3 GPCR (A 3 AR) is a potential therapeutic target for various conditions, including cancer, inflammation, and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias "fingerprints" for prototypical ribose containing A 3 AR agonists and rigidified (N)-methanocarba 59-N-methyluronamide nucleoside derivatives with regard to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 59-Nmethyluronamide nucleoside derivatives with significant N 6 or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in Å) and bias toward cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 59-N-methyluronamide nucleosides promote a progressive outward shift of the A 3 AR transmembrane domain 2, which may contribute to the subset of A 3 AR conformations stabilized on biased agonist binding

Molecular complexity from aromatics: Synthesis of embellished <i>endo </i>tricyclo[5.2.2.0^2,6] undecanes

873-875Synthesis of the tricyclic keto-epoxides 2 and 3 from the readily available aromatic precursors 4,5 respectively, via generation and interception of spiroepoxycyclohexa-2,4-dienones is described

Synthesis of embellished bicyclo[2.2.2]octenones and a sigmatropic 1,2-acyl shift in an excited state: a novel and stereoselective route to (±)-hirsutic acid C and complicatic acid

Formal syntheses of hirsutic acid C and complicatic acid via cycloaddition of cyclohexa-2,4-dienone with methyl methacrylate and a triplet sensitized 1,2-acyl shift are described. The X-ray crystal structure of one of the key intermediates is also reported.© Elsevie

Molecular complexity from aromatics. Cycloaddition of cyclohexa-2,4-dienones, sigmatropic 1,2-acyl shift and ring-closing metathesis: a new, efficient, and stereoselective synthesis of (±)-hirsutic acid C and medium ring carbocycles

A new, stereoselective formal synthesis of hirsutic acid and medium ring carbocyclic systems from salicyl alcohol is described. Cycloaddition between electron deficient partners such as cyclohexa-2,4-dienone and methylmethacrylate, triplet sensitized 1,2-acyl shift and ring-closing metathesis are the key features of our approach.© Elsevie