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A Guzman-Perez,
R T Wester,
M C Allen,
J A Brown,
A R Buchholz,
E R Cook, W W Day,
E S Hamanaka,
S P Kennedy,
D R Knight,
P J Kowalczyk,
R B Marala,
C J Mularski,
W A Novomisle,
R B Ruggeri,
W R Tracey,
R J Hill
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ABSTRACT: Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.
Bioorganic & Medicinal Chemistry Letters 04/2001; 11(6):803-7. · 2.55 Impact Factor
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ABSTRACT: CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.
Biopharmaceutics & Drug Disposition 11/1999; 20(7):319-26. · 2.07 Impact Factor
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ABSTRACT: To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and Cmax) data.
For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility.
Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 micrograms.hr/ml and the Cmax values ranged from 0.04 to 2.17 micrograms/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and Cmax results in ranges of 0.001 to 0.473 microgram.hr/ml, and 0.001 to 0.119 microgram/ml, respectively.
All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and Cmax corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.
Pharmaceutical Research 02/1998; 15(1):93-7. · 4.09 Impact Factor
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ABSTRACT: A simple and precise high-performance liquid chromatographic (HPLC) assay was developed and validated for the determination of a novel angiotensin II antagonist, 1-[5-(2-cyclopropyl-5,7-dimethyl-imidazo[4,5-b]pyridin-3-ylmethyl) thiophen-2-yl]cyclopent-3-enecarboxylic acid (CP-191,166, I), in dog and rat plasma. The internal standard (II, a saturated derivative of I) and analyte were extracted by liquid-liquid extraction using methyl tert.-butyl ether. Samples were analyzed by reversed-phase HPLC using a Zorbax C8 narrow-bore column with ultraviolet detection at 289 nm. The quantitation limit of I was 10 ng/ml and the calibration curve was linear over the range of 0.01-10.0 micrograms/ml (r2 > 0.99). In dog and rat plasma, intra- and inter-assay precision ranged from 0.00 to 3.36% and 0.00 to 4.95%, respectively. The average recoveries were similar (73%) for both I and II and the upper limit of quantification of I can be as high as 500 micrograms/ml. The method described has been successfully applied to the quantification of I in about 2000 dog and rat plasma samples over a nine-month period.
Journal of chromatography. B, Biomedical applications 02/1996; 675(2):265-71.
