Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues

Abstract

In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-amino-5'-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 microM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine bases were constructed and then glycosylated with appropriately protected alpha-ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED50s < or = 2.0 mg/kg, ip, and showed relatively mild side effects.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…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). Potency of nucleoside ADK inhibitors was significantly enhanced (e.g., 10-fold compared with 59-deoxy-59-aminoadenosine) in 6,8-disubstituted purine nucleosides (Bookser et al, 2005a).…”

“…Consequently, ADK inhibitors have been considered as a very attractive target for the treatment of various pain states, and proof of feasibility studies with prototypes of ADK inhibitors have demonstrated efficacy in several animal models of nociception (Keil and DeLander, 1994;Sawynok, 1995, 1998;Sawynok and Liu, 2003). Unfortunately, short half lives in vivo, poor bioavailability, lack of pharmacological selectivity, and potential to form cytotoxic metabolites limited further preclinical testing of those prototype inhibitors (Cottam et al, 1993;Wiesner et al, 1999;Ugarkar et al, 2000a). Therefore, most subsequent studies have focused on the structurally novel nucleoside (A-134974), nonnucleoside (ABT-702), and carbocyclic (A-286501) ADK inhibitors (Fig.…”

Proteome-wide Identification of Cellular Targets Affected by Bisindolylmaleimide-type Protein Kinase C Inhibitors

“…Inhibition of its activity enhances the release of adenosine from cells, and extracellular adenosine is known to act as a neuromodulator with potent anti-nociceptive and anti-inflammatory actions. Therefore, inhibition of AK activity is proposed as a therapeutic strategy for the treatment of pain, and inflammation and several potent inhibitors of AK activity have been reported (25)(26)(27). To analyze AK binding to BisIII beads, a myc-tagged version of AK was transiently expressed in COS-7 cells.…”

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

“…These compounds suppress seizures in rodent models, such as the bicuculline-induced seizure [249] and the maximal electroshock [170,250,251] model, presumably via an interaction of adenosine with cerebral A 1 R. For that reason and because upregulation of the enzyme AK is involved in epileptogenesis [171], AKIs are considered promising anticonvulsants [170,252,253].…”