Affiliation: Merck Research Laboratories
- Metabolic activation of a pyrazinone-containing thrombin inhibitor. Evidence for novel biotransformation involving pyrazinone ring oxidation, rearrangement, and covalent binding to proteinsRominder Singh
Department of Drug Metabolism, Merck Research Labs, West Point, Pennsylvania, USA
Chem Res Toxicol 16:198-207. 2003..Elucidation of the metabolic activation pathways of I provides structural guidance for the design of thrombin inhibitors with decreased potential for the generation of chemically reactive intermediates...
- Pharmacokinetics and metabolism of a RAS farnesyl transferase inhibitor in rats and dogs: in vitro-in vivo correlationR Singh
Department of Drug Metabolism, Merck Research Labs, West Point, Pennsylvania 19486, USA
Drug Metab Dispos 29:1578-87. 2001..Animal and human liver microsomal intrinsic clearance values were scaled to predict hepatic clearance and half-life in humans, and the predicted values were in good agreement to the in vivo data...
- Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamidesChristopher S Burgey
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Bioorg Med Chem Lett 13:1353-7. 2003..An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation...
- 9-hydroxyazafluorenes and their use in thrombin inhibitorsKenneth J Stauffer
Department of Medicinal Chemistry, Biological Chemistry, Pharmacology, Drug Metabolism, and Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
J Med Chem 48:2282-93. 2005..The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin...
- In vitro metabolism of a thrombin inhibitor and quantitation of metabolically generated cyanideC Charles Lin
Department of Drug Metabolism, Merck Research Laboratories, Merck and Co Inc, Merck Research Labs, BLA 33, P O Box 4, PA 19486, USA
J Pharm Biomed Anal 39:1014-20. 2005..However, the HPLC assay was the preferred method for the evaluation of cyanide formation in vitro due to its sensitivity, reliability, and ease of use...
- Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridinesChristopher S Burgey
Departments of Medicinal Chemistry, Biological Chemistry, Drug Metabolism, Molecular Systems, Structural Biology, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
J Med Chem 46:461-73. 2003..e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives...
- Bioactivation of the 3-amino-6-chloropyrazinone ring in a thrombin inhibitor leads to novel dihydro-imidazole and imidazolidine derivatives: structures and mechanism using 13C-labels, mass spectrometry, and NMRRaju Subramanian
Department of Drug Metabolism, WP75 100, Merck Research Laboratories, West Point, PA 19486, USA
Drug Metab Dispos 31:1437-47. 2003..The metabolite structures described here illustrate the rich metabolic chemistry of the amino-pyrazinone heterocycle...
- Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activityChristopher R Gibson
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
Drug Metab Dispos 33:1044-51. 2005..It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A...