Robert T. Lum

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.

SYNTHESIS AND ANTIVIRAL ACTIVITY OF A NOVEL CLASS OF HIV-1 PROTEASE INHIBITORS CONTAINING A HETEROCYCLIC P1'-P2' AMIDE BOND ISOSTERE

A novel series of hydroxyethylene-based peptidomimetics that contain 2-substituted nitrogen heterocycles as P1′-P2′ amide bond isosteres has been prepared and evaluated as inhibitors of HIV-1 protease and in vitro HIV-1 replication. Many of these compounds exhibit inhibition constants in the low to subnanomolar range. Structure-activity relationships are discussed.

In vitro and in vivo prevention of HIV protease inhibitor‐induced insulin resistance by a novel small molecule insulin receptor activator

Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin‐stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non‐peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin‐stimulated GLUT4 at the plasma membrane, and enhanced insulin‐stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs.

5-Substituted isophthalamides as insulin receptor sensitizers

A novel series of 5-substituted isophthalamides and their structure-activity relationship as insulin receptor sensitizers is discussed.