South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase

Abstract

Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. Based on the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5′-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5′-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N6-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ~100 nM), while the 5′-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5′-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy.

Polypharmacology of conformationally locked methanocarba nucleosides

“…Recently, (N)- and (S)-methanocarba nucleosides MRS4203 11 and MRS4380 12 were also introduced as inhibitors of adenosine kinase (ADK), another conventional purine target [51]. Inhibitors of h ADK have pronounced antiepileptic and antiepileptogenic effects [52].…”

“…Inhibitors of h ADK have pronounced antiepileptic and antiepileptogenic effects [52]. Compounds 11 and 12 were comparable in potency to a standard ADK carbocyclic nucleoside inhibitor A-134974 [51]. A year after the first report of methanocarba nucleosides by Marquez and colleagues [53], Altmann et al independently disclosed that the stability of oligodeoxynucleotide heteroduplexes involving (N)-methanocarba-T (T N ) increased, and the (S)-methanocarba-T destabilized the heteroduplex [54,55].…”

Ocular Purine Receptors as Drug Targets in the Eye

“…62 Nevertheless, adenosine kinase inhibitors have their own side effects, led to the discontinuation of past clinical trials of centrally-acting inhibitors. 63 At the A 3 AR, there is evidence that topically applied selective antagonists reduce IOP, and topically applied selective agonists increase IOP. 33,[64][65][66] The mechanistic basis for this action is that the A 3 AR is coupled to a chloride channel in the nonpigmented ciliary epithelial layer, such that its activation causes inflow leading to a rise in IOP.…”

Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists

“…37,38 The pyrimidine core in 28 was constructed in excellent yield by heating 26 with ammonium hydroxide. The C4-oxygen of the pyrimidine was activated to 2,4,6-triisopropylbenzenesulfonate and reacted with a nucleophile, in this case methoxylamine and benzyloxyamine to give 29a and b , respectively.…”