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1.
Bioorg Med Chem Lett ; 11(14): 1817-21, 2001 Jul 23.
Article in English | MEDLINE | ID: mdl-11459639

ABSTRACT

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Alkyl and Aryl Transferases/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Amino Acids/chemistry , Animals , Cells, Cultured , Dogs , Enzyme Inhibitors/chemical synthesis , Half-Life , Inhibitory Concentration 50 , Metabolic Clearance Rate/physiology , Molecular Conformation , Protein Binding/drug effects , Rats
2.
Bioorg Med Chem Lett ; 11(4): 537-40, 2001 Feb 26.
Article in English | MEDLINE | ID: mdl-11229765

ABSTRACT

The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmacokinetic profile relative to the parent 1-aryl-2-piperazinones.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Piperazines/pharmacology , Animals , Dogs , Enzyme Inhibitors/pharmacokinetics , Farnesyltranstransferase , Structure-Activity Relationship
3.
Org Lett ; 2(22): 3473-6, 2000 Nov 02.
Article in English | MEDLINE | ID: mdl-11082012

ABSTRACT

[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indicators and Reagents , Models, Molecular , Molecular Conformation , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 10(14): 1527-30, 2000 Jul 17.
Article in English | MEDLINE | ID: mdl-10915042

ABSTRACT

An efficient combination solution-phase/solid-phase route enabling the diversification of the P1', P2', and P3 subsites of indinavir has been established. The synthetic sequence can facilitate the rapid generation of HIV protease inhibitors possessing more favorable pharmacokinetic properties as well as enhanced potencies. Multiple compound dosing in vivo may also accelerate the identification of potential drug candidates.


Subject(s)
Combinatorial Chemistry Techniques , HIV Protease Inhibitors/chemistry , Indinavir/analogs & derivatives , Indinavir/chemistry , Animals , Cell Line , Dogs , HIV Protease/metabolism , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Humans , Indinavir/chemical synthesis , Indinavir/pharmacokinetics , Indinavir/pharmacology , Models, Molecular , Molecular Conformation , Molecular Structure , T-Lymphocytes
5.
J Clin Pharmacol ; 40(1): 74-83, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10631625

ABSTRACT

Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma.


Subject(s)
Serotonin Receptor Agonists/adverse effects , Serotonin Receptor Agonists/pharmacokinetics , Triazoles/adverse effects , Triazoles/pharmacokinetics , Adult , Blood Pressure/drug effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Placebos , Serotonin Receptor Agonists/administration & dosage , Time Factors , Triazoles/administration & dosage , Tryptamines
6.
Br J Clin Pharmacol ; 47(4): 373-8, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10233200

ABSTRACT

AIMS: The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied. METHODS: In a randomized, crossover study with four periods, twenty-four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1-4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively. RESULTS: The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15-mg rizatriptan were 16, 33, 72, and 127 ng ml-1 h, respectively, in males; and 19, 42, 97, and 161 ng ml-1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was approximately 40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min-1, respectively, in males; and 821 and 174 ml min-1, respectively, in females. CONCLUSIONS: The disposition kinetics of oral rizatriptan were linear for doses of 2. 5-10 mg in males, and for doses of 2.5-5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.


Subject(s)
Serotonin Receptor Agonists/pharmacokinetics , Triazoles/pharmacokinetics , Administration, Oral , Animals , Cross-Over Studies , Female , Male , Mice , Sex Factors , Triazoles/administration & dosage , Triazoles/adverse effects , Tryptamines
7.
Biopharm Drug Dispos ; 19(9): 577-81, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9872339

ABSTRACT

The pharmacokinetics and tolerability of intravenous (i.v.) rizatriptan (MK-0462), a novel 5-HT1D/1B receptor agonist for the acute oral treatment of migraine, were examined in an open, single-dose, four-period, randomized crossover study in healthy females. Results of this study indicated that i.v. rizatriptan (0.5-5 mg) was well tolerated. The disposition kinetics of rizatriptan were linear for i.v. doses up to and including 2.5 mg. Relative to the 0.5 mg dose, geometric mean dose-adjusted AUC ratios were 1.04, 1.09, and 1.18 for 1, 2.5, and 5 mg doses, respectively. Apparent plasma clearance (Cl) ranged between 859 and 941 mL min(-1) from 0.5 to 2.5 mg, but dropped to slightly below 800 mL min(-1) for the 5 mg dose. Therefore, the elimination of rizatriptan appears somewhat dose dependent at the high end of this dose range. Mean plasma half-life (t1/2) was 1.5-2.2 h across all doses while mean residence time in the body (MRT) and steady state volume of distribution (Vss) of rizatriptan remained relatively invariant across doses. Urinary excretion of rizatriptan (Ue) ranged from 14.5 to 34.6% of dose.


Subject(s)
Serotonin Receptor Agonists/pharmacokinetics , Triazoles/pharmacokinetics , Adult , Analysis of Variance , Cross-Over Studies , Dizziness/chemically induced , Female , Humans , Injections, Intravenous , Migraine Disorders/metabolism , Serotonin Receptor Agonists/adverse effects , Serotonin Receptor Agonists/blood , Tachycardia/chemically induced , Triazoles/adverse effects , Triazoles/blood , Tryptamines
8.
J Pharm Biomed Anal ; 15(12): 1893-901, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9278895

ABSTRACT

New drug candidates are being synthesized at an ever increasing rate and, until recently, the pharmacokinetics of only a few of these could be evaluated. Our laboratory is taking a novel approach to rapid multiple pharmacokinetic screening of potential drug candidates in which mixtures of new substances are co-administered to animals and analyzed simultaneously in plasma using liquid chromatography with tandem MS/MS detection in conjunction with a Prospekt automated on-line solid-phase extraction system. Plasma is sampled via an autosampler and extracted by the Prospekt with the eluent being introduced directly via a reverse phase HPLC column and a heated nebulizer interface to the mass spectrometer. Generic extraction and chromatographic conditions generally give good recoveries. The chromatographic run-times are less than 8 min. The accuracy and precision of these assays are carefully controlled with recoveries generally in the range 80-120% and coefficients of variation less than 20%. Lower quantifiable limits range from 2.5 to 5 ng ml-1. This approach considerably reduces the number of animals needed to screen drug candidates and its power is illustrated by determination of the pharmacokinetics of 10 substances after their simultaneous administration to dogs.


Subject(s)
Autoanalysis/instrumentation , Chromatography, Liquid/methods , Mass Spectrometry/methods , Pharmaceutical Preparations/analysis , Animals , Atmospheric Pressure , Dogs , Male , Online Systems , Quality Control , Reproducibility of Results
9.
Rapid Commun Mass Spectrom ; 11(1): 17-23, 1997.
Article in English | MEDLINE | ID: mdl-9050259

ABSTRACT

Liquid chromatography, combined with tandem mass spectrometry (LC/MS/MS) has been rapidly embraced by the pharmaceutical industry as the definitive method for the determination of drug levels in biological fluids obtained from pharmacokinetic and toxicological studies. This technique has proved to be reliable, accurate and precise for the determination of drugs and related substances (e.g. metabolites and isotope-labeled compounds) in support of preclinical and clinical studies. Our group has recently expanded the use of quantitative LC/MS/MS into the area of discovering new substances as potential drug candidates. When used as an accurate mass detector, triple quadrupole instruments have the ability to simultaneously and specifically detect minute quantities of closely-related drug substances in the extracts of biological fluids. Analytical procedures have been developed and validated that simultaneously determine plasma concentrations of up to 12 drug candidates over a concentration range of 1-1000 ng mL-1 in single analytical occasions. This approach is used to support drug discovery by rapidly providing pharmacokinetic data to a wide range of compounds following either the administration of multiple compounds to single animals, or by increasing the speed and efficiency of analyzing samples following the administration of single compounds to multiple animals. Currently, we have screened over 400 compounds in two different target classes in a period of 24 weeks. A standard operating procedure defining the acceptability of quality control data obtained during such screening experiments is described.


Subject(s)
Pharmaceutical Preparations/analysis , Animals , Area Under Curve , Chromatography, Liquid , Dogs , Mass Spectrometry , Pharmacokinetics , Quality Control , Rats
10.
J Chromatogr A ; 726(1-2): 115-24, 1996 Mar 01.
Article in English | MEDLINE | ID: mdl-8900521

ABSTRACT

The 5HT1D agonist sumatriptan is efficacious in the treatment of migraines. MK-462 is a drug of the same class which is under development in our laboratories. Bioanalytical methods of high efficiency, specificity and sensitivity were required to support the preclinical and clinical programs. These assays were based on HPLC with tandem MS-MS detection. MK-462 and sumatriptan were extracted using an automated solid-phase extraction technique on a C2 Varian Bond-Elut cartridge. The n-diethyl analogues of MK-462 and sumatriptan were used as internal standards. The analytes were chromatographed using reversed-phase (nitrile) columns coupled via a heated nebulizer interface to an atmospheric pressure chemical ionization source. The chromatographic run times were less than 7 min. Both methods were precise, accurate and selective down to plasma concentrations of 0.5 ng/ml. The assay for MK-462 was adapted to separately monitor the unlabeled and 14C-labeled species of the drug following intravenous administration of radiolabeled material to man.


Subject(s)
Chromatography, High Pressure Liquid/methods , Mass Spectrometry/methods , Serotonin Receptor Agonists/blood , Sumatriptan/blood , Triazoles/blood , Humans , Pressure , Reference Values , Reproducibility of Results , Serotonin Receptor Agonists/pharmacology , Sumatriptan/pharmacology , Triazoles/pharmacology , Tryptamines
11.
J Pharm Biomed Anal ; 12(5): 705-12, 1994 May.
Article in English | MEDLINE | ID: mdl-7948192

ABSTRACT

MK-434 is a new 5 alpha-reductase inhibitor. A sensitive and specific assay based on combined liquid chromatography-mass spectrometry (LC-MS) has been developed for the determination of this compound in plasma. The analyte was isolated from plasma by solid-phase extraction on a C18 cartridge. A related substance, L-654,066, was used as the internal standard. Extracts were separated on a 5-cm C18-reversed-phase high performance liquid chromatography column interfaced via the heated nebulizer probe to a corona discharge chemical ionization source. The mass spectrometer was operated in the positive ion MS-MS mode. The method had sufficient sensitivity, precision, accuracy, and selectivity for the analysis of clinical samples containing MK-434 and its two principal metabolites at concentrations in the range 0.5-50 ng ml-1. The chromatographic run time was < 5 min.


Subject(s)
5-alpha Reductase Inhibitors , Azasteroids/blood , Finasteride/analogs & derivatives , Calibration , Chromatography, High Pressure Liquid , Finasteride/blood , Mass Spectrometry , Radioimmunoassay , Reference Standards , Reproducibility of Results
12.
J Chromatogr ; 631(1-2): 255-9, 1993 Feb 12.
Article in English | MEDLINE | ID: mdl-8450018

ABSTRACT

A method of analysis has been developed to quantify promethazine in human serum with a sensitivity that was suitable for bioavailability studies following a 50.0-mg rectal dose. The limit of quantification from 1.0 ml of serum for promethazine using electrochemical detection was 0.200 ng/ml. At this concentration, the total coefficient of variation obtained from seven replicates over the course of three days of validation was 7.53%. The amount of serum required, the ease of sample preparation and the precision of the method at the limit of quantification demonstrated an improvement over previous assays. A validation study was completed that included an evaluation of recovery, ruggedness, linearity of response, accuracy, precision, sensitivity, stability and selectivity. The method was then used to determine promethazine serum levels in a 36-subject bioavailability study following a 50.0-mg suppository dose.


Subject(s)
Chromatography, High Pressure Liquid/methods , Promethazine/blood , Electrochemistry , Humans , Reproducibility of Results
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