Pharmacokinetics, Pharmacodynamics, and Safety of a Lipid-Lowering Adenosine A1 Agonist, RPR749, in Healthy Subjects

Abstract

RPR749 and its methylated metabolite are orally active and selective adenosine A(1) agonists that can inhibit lipolysis and lower plasma triglyceride levels in a variety of animal models. RPR749 also appears to lower free fatty acid (FFA) and insulin levels and may have additional lipid-modifying effects. This double-blind, single increasing-dose, placebo-controlled, parallel group, randomized study, the first done in humans, evaluated the safety, pharmacokinetics, and pharmacodynamics (effect on FFA) after a single oral dose of up to 200 mg RPR749 or placebo. Six parallel groups of 8 healthy men (6 active and 2 placebo/group) were enrolled in the study. Plasma samples were collected for up to 72 hours post-dose. RPR749 and its metabolite RPR772 concentrations were measured by a validated LC/MS/MS method with a minimal quantifiable limit of 1 ng/mL. RPR749 was safe and well tolerated as a single oral dose up to 200 mg. The mean plasma concentrations of RPR749 were approximately 30-fold higher than the mean RPR772 plasma concentrations. The mean terminal half-life (t(1/2)) of RPR749 and RPR772 were similar (approximately 16.4 hours). Mean values for serum insulin, triglycerides, glycerol, and blood glucose remained within normal ranges. Mean FFA concentrations in serum decreased in all treatment groups with the maximal decrease in the 200-mg dose group. In conclusion, RPR749 has the ability to reduce circulating levels of FFA that can be related to plasma RPR749 concentrations and thus possesses pharmacological properties that may be beneficial in treating coronary artery diseases and hyperlipidemia.

Bone Marrow and Adipose Tissue Adenosine Receptors Effect on Osteogenesis and Adipogenesis

“…As shown in Table 2 , several A1AR agonists, including SDZWAG994, ARA and RPR749, have been evaluated in humans as antilipolytic agents for hypertriglyceridemia [ 88 , 89 , 90 ]. RPR749 is an orally active A1AR agonist.…”

“…In a double-blind, single increasing dose, placebo-controlled, parallel group randomized study, six parallel groups of eight men (six individuals in the active arm and two in the placebo arm in each group) were given RPR749 or control as a single dose. The average free fatty acid concentration in the serum decreased in all treatment groups [ 90 ]. Unfortunately, A1AR agonists have significant side effects, including in the heart and kidney, and also become desensitized after repeated exposure.…”

Recent developments in adenosine receptor ligands and their potential as novel drugs

“…The A 1 AR-selective agonist GW493838 ( 7 ) was also under evaluation for pain management. RPR749 (Aventis) and its methylated metabolite are orally active and selective adenosine A 1 AR agonists that inhibit lipolysis in adipocytes and lower plasma triglyceride levels [95]. GS-9667 ( 11 , CVT-3619), a partial agonist of the A 1 AR, is in development as an antilipolytic agent.…”

Purinergic Receptors in Adipose Tissue As Potential Targets in Metabolic Disorders

“…There is a consensus that A 1 R regulates lipolysis and therefore FFAs levels, which play a significant role in the pathogenesis of insulin resistance, diabetes, and cardiovascular diseases ( Dhalla et al, 2009 ; Antonioli et al, 2015 ). Several A 1 R agonists, e.g., SDZWAG994 ( Ishikawa et al, 1998 ), ARA ( Zannikos et al, 2001 ), and RPR749 ( Shah et al, 2004 ), have been clinically evaluated as anti-lipolytic agents for the treatment of hypertriglyceridemia and type-2 diabetes. Though, development of full A 1 R agonists has been limited by (i) the debilitating side effects induced by the activation of the receptors in heart and kidney of animal models ( Belardinelli et al, 1989 ; Wu et al, 2001 ); and (ii) a well-characterized desensitization of the receptor after repeated exposure to full agonists ( Hoffman et al, 1986 ; Dhalla et al, 2007b ).…”