ABSTRACT
SCH 900567 is a specific inhibitor of tumor necrosis factor-alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [(3) H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope-labeled [(13) C3 , (15) N]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [(13) C3 , (15) N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [(14) C]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [(14) C]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Hydantoins/chemical synthesis , Isoindoles/chemical synthesis , Radiopharmaceuticals/chemical synthesis , ADAM17 Protein , Carbon Radioisotopes/chemistry , Hydantoins/pharmacokinetics , Isoindoles/pharmacokinetics , Nitrogen Radioisotopes/chemistry , Tritium/chemistryABSTRACT
The application of parallel synthesis is an efficient approach to explore the chemical space and to rapidly develop meaningful structure activity relationship (SAR) data for drug discovery programs. However, the effectiveness of the parallel synthesis requires a high throughput purification workflow that can process a large number of crude samples within a meaningful time frame. This paper describes a high throughput purification platform that has been adopted at Merck's Rahway research site. The platform includes the evaluation of crude samples, mass-directed HPLC purification, fraction analysis, compound registration, final compound purity assessment and assay distribution. Assisting with the sample tracking and the data management is the internally designed laboratory information management system, Light Automation Framework (LAF). Using this process and the tools described herein, the group has successfully achieved purities of 95% or greater for 90% of samples.
Subject(s)
Drug Discovery/methods , High-Throughput Screening Assays/methods , Pharmaceutical Preparations/isolation & purification , Chromatography, High Pressure Liquid , Drug Discovery/instrumentation , Equipment Design , High-Throughput Screening Assays/instrumentation , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/chemistry , Quality Control , Structure-Activity RelationshipABSTRACT
Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.
Subject(s)
Aristolochic Acids/chemical synthesis , CDC2 Protein Kinase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Quinolines/chemical synthesis , Aristolochic Acids/chemistry , Aristolochic Acids/pharmacology , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
The 70% aqueous methanolic extract of the Chinese plant Aristolochia manshuriensis was found to contain two novel substituted phenanthrene compounds, SCH 546909 (1), and another phenanthrene glycoside (2). The structures of 1 and 2 were established based on NMR studies. They were identified as inhibitors of the CDK2 enzyme. Compound 1 was found to be a potent inhibitor of the CDK2 enzyme with an IC50 of 140 nM, whereas compound 2 was found to be less active with an IC50 of >10 microM.