Adenosine Kinase Inhibitors. 1. Synthesis, Enzyme Inhibition, and Antiseizure Activity of 5-Iodotubercidin Analogues

Abstract

Adenosine receptor agonists produce a wide variety of therapeutically useful pharmacologies. However, to date they have failed to undergo successful clinical development due to dose-limiting side effects. Adenosine kinase inhibitors (AKIs) represent an alternative strategy, since AKIs may raise local adenosine levels in a more site- and event-specific manner and thereby elicit the desired pharmacology with a greater therapeutic window. Starting with 5-iodotubercidin (IC50 = 0.026 microM) and 5'-amino-5'-deoxyadenosine (IC50 = 0.17 microM) as lead inhibitors of the isolated human AK, a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5'-Amino-5'-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AKIs reported to date (IC50S < 0.001 microM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock (MES) induced seizure assay.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…The ADK inhibitors 5-iodotubercidin, 59-amino-59-deoxyadenosine, 59-deoxy-5-iodotubercidin, as well as novel classes of ADK inhibitors such as 4-(N-phenylamino)-5-phenyl-7-(59-deoxyribofuranosyl)pyrrolo[2,3-day] pyrimidine (GP683), were shown to inhibit seizures in the maximal electroshock (MES) model in rats (Wiesner et al, 1999). Among those pyrrolo[2,3-day]pyrimidine nucleoside analogs, the 59-amino-59-deoxy analogs of 5-bromo-and 5-iodotubercidin exhibited the highest potency and efficacy in the MES model (Ugarkar et al, 2000b). Although none of those compounds met a safety, efficacy, and side effect profile suitable for further drug development (Ugarkar et al, 2000a), substitution of the tubercidin molecule with aromatic rings at the N4 and C5 positions yielded highly potent ADK inhibitors with efficacy in the MES model and reduced side effects (Ugarkar et al, 2000a).…”

An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

“…In deep layers of the ventral horn, adenosine likewise inhibits excitatory synaptic transmission, potentially facilitating neuroprotection and/or motor impairment (Miyazaki et al, 2008;Carlsen and Perrier, 2014). Moreover, AK inhibitors release adenosine from the spinal cord (Golembiowska et al, 1995;, and intrathecal administration of these inhibitors yields analgesia (Poon and Sawynok, 1995;McGaraughty et al, 2001;Zhu et al, 2001), although some nucleoside AK inhibitors, such as 5-iodotuberdicin and 5'-amino-5'-deoxyadenosine, have therapeutic limitations because of its adverse effects, poor oral bioavailability or a short half-life in vivo (Ugarkar et al, 2000;McGaraughty et al, 2005).…”

Deciphering ligand dependent degree of binding site closure and its implication in inhibitor design: A modeling study on human adenosine kinase

“…Inhibition of AK results in increased intracellular adenosine, which passes out of the cell via passive diffusion or via nucleoside transporter(s) to activate nearby cell-surface adenosine receptors and produce a wide variety of therapeutically beneficial activities against the said diseases [10,11]. There are a number of reports on synthesis, SAR [12,13] and QSAR studies of nucleosidic analogues as AK inhibitors [14,15]. Nucleoside kinases, such as AK, cytidine kinase, thymidine kinase, catalyze phosphorylation of a variety of nucleosides, including nucleoside-based drugs, giving rise to nucleoside-5 0 -O-phosphates which are incorporated into RNA or DNA via the corresponding triphosphates [16].…”