Marek G. Nelson

Synthesis and activity of 2,6,9-trisubstituted purines

The preparation of a series of 2,6,9-trisubstituted purines and the structure-activity data for the inhibition of cyclin dependent kinase, CDK2 are presented.

A New Structural Class of Proteasome Inhibitors that Prevent NF-κB Activation

Abstract The multicatalytic proteinase or proteasome is a highly conserved cellular structure that is responsible for the ATP-dependent proteolysis of many proteins involved in important regulatory cellular processes. We have identified a novel class of inhibitors of the chymotrypsin-like proteolytic activity of the 20S proteasome that exhibit ic 50 values ranging from 0.1 to 0.5 μg/mL (0.1 to 1 μM). In cell proliferation assays, these compounds inhibit growth with an ic 50 ranging from 5 to 10 μg/mL (10–20 μM). A representative member of this class of inhibitors was tested in other biological assays. CVT-634 (5-methoxy-1-indanone-3-acetyl-leu- d -leu-1-indanylamide) prevented lipopolysaccharide (LPS), tumor necrosis factor (TNF)-, and phorbol ester-induced activation of nuclear factor κB (NF-κB) in vitro by preventing signal-induced degradation of IκB-α. In these studies, the IκB-α that accumulated was hyperphosphorylated, indicating that CVT-634 did not inhibit IκB-α kinase, the enzyme responsible for signal-induced phosphorylation of IκB-α. In vivo studies indicated that CVT-634 prevented LPS-induced TNF synthesis in a murine macrophage cell line. In addition, in mice pretreated with CVT-634 at 25 and 50 mg/kg and subsequently treated with LPS, serum TNF levels were significantly lower (225 ± 59 and 83 ± 41 pg/mL, respectively) than in those mice that were treated only with LPS (865 ± 282 pg/mL). These studies suggest that specific inhibition of the chymotrypsin-like activity of the proteasome is sufficient to prevent signal-induced NF-κB activation and that the proteasome is a novel target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent upon the activation of NF-κB.

A comparison of an A1 adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig.

The purpose of this study was to compare the pharmacological properties (i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A1 adenosine receptor (A1 receptor) agonist, N‐(3(R)‐tetrahydrofuranyl)‐6‐aminopurine riboside (CVT‐510), and the prototypical calcium channel blocker diltiazem. In the atrial‐paced isolated heart, CVT‐510 was approximately 5 fold more potent to prolong the stimulus‐to‐His bundle (S–H interval), a measure of slowing AV nodal conduction (EC50=41 nM) than to increase coronary conductance (EC50=200 nM). At concentrations of CVT‐510 (40 nM) and diltiazem (1 μM) that caused equal prolongation of S–H interval (∼10 ms), diltiazem, but not CVT‐510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT‐510 shortened atrial (EC50=73 nM) but not the ventricular monophasic action potentials (MAP). In atrial‐paced anaesthetized guinea‐pigs, intravenous infusions of CVT‐510 and diltiazem caused nearly equal prolongations of P–R interval. However, diltiazem, but not CVT‐510, significantly reduced mean arterial blood pressure. Both CVT‐510 and diltiazem prolonged S–H interval, i.e., slowed AV nodal conduction. However, the A1 receptor‐selective agonist CVT‐510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT‐510 did not affect the ventricular action potential, it is unlikely that this agonist will have a proarrythmic action in ventricular myocardium.

Selective inhibition of the chymotrypsin-like activity of the 20S proteasome by 5-methoxy-1-indanone dipeptide benzamides

Potent inhibitors of the 20S proteasome that contain a novel indanone head group coupled to di and tripeptides are described. These compounds are the first proteasome inhibitors have demonstrated high selectivity for the chymotrypsin-like activity of the 20S proteasome.