Toward a Stable and Potent Coenzyme A-Targeting Antiplasmodial Agent: Structure-Activity Relationship Studies of N-Phenethyl-α-methyl-pantothenamide.

Pantothenamides (PanAms) are potent antiplasmodials with low human toxicity currently being investigated as antimalarials with a novel mode of action. These structural analogues of pantothenate, the vitamin precursor of the essential cofactor coenzyme A, are susceptible to degradation by pantetheinase enzymes present in serum. We previously discovered that α-methylation of the ß-alanine moiety of PanAms increases their stability in serum and identified N-phenethyl-α-methyl-pantothenamide as a pantetheinase-resistant PanAm with potent, on-target, and selective antiplasmodial activity. In this study, we performed structure-activity relationship investigations to establish whether stability and potency can be improved further through alternative modification of the scissile amide bond and through substitution/modification of the phenyl ring. Additionally, for the first time, the importance of the stereochemistry of the α-methyl group was evaluated in terms of stability versus potency. Our results demonstrate that α-methylation remains the superior choice for amide modification, and that while monofluoro-substitution of the phenyl ring (that often improves ADME properties) was tolerated, N-phenethyl-α-methyl-pantothenamide remains the most potent analogue. We show that the 2S,2'R-diastereomer is far more potent than the 2R,2'R-diastereomer and that this cannot be attributed to preferential metabolic activation by pantothenate kinase, the first enzyme of the coenzyme A biosynthesis pathway. Unexpectedly, the more potent 2S,2'R-diastereomer is also more prone to pantetheinase-mediated degradation. Finally, the results of in vitro studies to assess permeability and metabolic stability of the 2S,2'R-diastereomer suggested species-dependent degradation via amide hydrolysis. Our study provides important information for the continued development of PanAm-based antimalarials.

Direct Recording of Cardiac and Renal Sympathetic Nerve Activity Shows Differential Control in Renovascular Hypertension.

There is increasing evidence that hypertension is initiated and maintained by elevated sympathetic tone. Increased sympathetic drive to the heart is linked to cardiac hypertrophy in hypertension and worsens prognosis. However, cardiac sympathetic nerve activity (SNA) has not previously been directly recorded in hypertension. We hypothesized that directly recorded cardiac SNA levels would be elevated during hypertension and that baroreflex control of cardiac SNA would be impaired during hypertension. Adult ewes either underwent unilateral renal artery clipping (n=12) or sham surgery (n=15). Two weeks later, electrodes were placed in the contralateral renal and cardiac nerves to record SNA. Baseline levels of SNA and baroreflex control of heart rate and sympathetic drive were examined. Unilateral renal artery clipping induced hypertension (mean arterial pressure 109±2 versus 91±3 mm Hg in shams; P<0.001). The heart rate baroreflex curve was shifted rightward but remained intact. In the hypertensive group, cardiac sympathetic burst incidence (bursts/100 beats) was increased (39±14 versus 25±9 in normotensives; P<0.05), whereas renal sympathetic burst incidence was decreased (69±20 versus 93±8 in normotensives; P<0.01). The renal sympathetic baroreflex curve was shifted rightward and showed increased gain, but there was no change in the cardiac sympathetic baroreflex gain. Renovascular hypertension is associated with differential control of cardiac and renal SNA; baseline cardiac SNA is increased, whereas renal SNA is decreased.