Synthesis of 3 H, 2 H4 , and 14 C-MK 3814 (preladenant).

MK 3814 is a potent and selective antagonist of the A2a receptor. A2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [3 H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [14 C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [2 H4 ]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method. This paper discusses the synthesis of 3 isotopically labelled forms of MK 3814.

Synthesis of (3) H, (2) H4 and (14) C-SCH 417690 (Vicriviroc).

Vicriviroc or SCH 417690 is a potent and selective antagonist of the CCR5 receptor. CCR5 receptor antagonists have the potential for the treatment of HIV infections. Four distinct isotopically labelled forms of SCH 417690 were synthesized. Low specific activity [(3) H]SCH 417690 was prepared for a preliminary absorption, distribution, metabolism and excretion evaluation of the compound and [(14) C]SCH 417690 for more definitive absorption, distribution, metabolism and excretion work, including an absorption, metabolism and excretion study in man. In addition, high specific activity [(3) H]SCH 417690 was prepared for CCR5 receptor binding work and [(2) H4 ]SCH 417690 was prepared as an internal standard for a liquid chromatography-mass spectrometry bioanalytical method. The paper discusses the synthesis of four isotopically labelled forms of SCH 417690.

Synthesis of 3H, 13C,2H3,15N and 14C-labelled SCH 466036, a histamine 3 receptor antagonist.

The synthesis of [(3)H]SCH 466036, [Me-(3)H3]SCH 466036, [(13)C,(2)H3,(15)N]SCH 466036 and [(14)C]SCH 466036 is described. [(3)H]SCH 466036 was prepared in two steps via Raney Ni-catalysed exchange with tritiated water. [Me-(3)H3]SCH 466036 was prepared in a single step from [(3)H]methyl iodide in 45% yield. [(13)C,(2)H3,(15)N]SCH 466036 was prepared in two steps from [(15)N]hydroxylamine and [(13)C,(2)H3]methyl iodide with an overall yield of 16%. [(14)C]SCH 466036 was prepared in seven steps from [(14)C]potassium cyanide in an overall yield of 13%.

Appropriate column configurations for the rapid analysis and semipreparative purification of the radiolabeled drug flutamide by high-performance liquid chromatography.

Flutamide, marketed as Eulexin, is used for treatment of metastic prostatic carcinoma. Purity of a radiolabeled batch for metabolism studies was first determined by reversed-phase HPLC on a 5 microm, 150x4.6 mm analytical column. The separation was then scaled up to give a semipreparative column (5 microm, 250x10 mm) purification procedure. Fraction analysis was done on a short rapid analysis (5 microm, 50x3.0 mm) column. Analysis of the final product was performed on the analytical column. All columns were YMC-Pack ODS-AQ. The analytical work involved large mass injections in order to have the required amounts of radioactivity needed for accurate impurity profile determinations, and the preparative work involved masses much larger than the calculated scale-up values. Ultraviolet and radiochromatograms of the drug on the various column configurations are compared. A 95.7% recovery of product was obtained, with radiochemical purity increased from 95.0 to 99.8%.

Use of fluorine-containing stationary phases for the separation of an alkyl bromide from its hydrocarbon analog by high-performance liquid chromatography.

Radiolabelled Sch 13835, an inhibitor of platelet derived growth factor, was prepared by catalytic hydrogenolysis of a benzyl bromide precursor with tritium gas. Regular and deactivated reversed-phase HPLC stationary phases gave poor peak shapes and little resolution of Sch 13835 and the benzyl bromide precursor. Fluorodecyl and fluoroether stationary phases in the analytical reversed-phase mode gave baseline separation using organic-aqueous (no buffers) mobile phases. Elution orders were reversed on either phase by a change in the organic component from methanol to acetonitrile. The product is unstable in aqueous (or other protic) solvents, forming a ring-opened acid. Conditions were developed to successfully purify the compound by reversed-phase HPLC with minimal decomposition. A second analytical HPLC assay was developed using normal-phase solvents on a fluoroether stationary phase.

Power spectral analysis of heart rate variability after biofeedback training.

This study investigated the effects of biofeedback/self-management training on heart rate variability (HRV) in six sudden cardiac arrest survivors. The physiological-theoretical basis of the training was cognitively inducing respiratory sinus arrhythmia. Power spectral analyses and nonspectral analyses (Kleiger, Magid, SCANN, BB50 measures) of HRV measured before and after 5 weeks of biofeedback training are described. The posttraining Kleiger measure of mean HRV increased compared to the pretraining mean HRV (159 +/- 37 ms vs 147 +/- 38 ms). After training, the high frequency components (0.27-0.30 Hz) of the power density spectra were markedly increased, suggesting an increase of respiratory-driven parasympathetic activity. After training, the low frequency components (0.05 Hz) were slightly decreased, suggesting a decrease in sympathetic activity. The increases noted in the high frequency components were more striking during 9 hours at night than during the day. These data indicate that subjects who have had sudden cardiac arrest can, through biofeedback/self-management, cognitively increase their HRV over a 5-week period, consequently increasing parasympathetic activity.

Self-management of hypertension: predictors of success in diastolic blood pressure reduction.

The purpose of this study was to determine which borderline hypertension subjects could succeed in self-regulating blood pressure, and to distinguish the psychologic and physiologic variables that predicted success. Thirty-four white, male, unmedicated, borderline hypertensive subjects participated in a 14-session biofeedback/cognitive self-management training program. Of these, 22 exited with diastolic pressure below 90 mm Hg; 12 exited equal to or above 90 mm Hg. Both groups exited with scores markedly lower on the Symptoms Checklist-90 (SCL-90). The successful group began and ended on all cognitive/affective subscales at a lower level than the unsuccessful group. A discriminant analysis revealed that lower scores on the SCL-90, lower systolic blood pressures, and higher heart rates during a mental task at the beginning of treatment distinguished those who succeeded in self-regulation from those who could not succeed. The possible mechanisms for blood pressure control/change as a consequence of biofeedback are discussed.